Collagen Signaling in Cancer

C H A P T E R

7 Collagen Signaling in Cancer Huocong Huang*, Marietta Eva Kovacs*, Kristina Y. Aguilera†, Rolf A. Brekken* *

Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas, Dallas, TX, United States † Department of Pathology, University of California, Los Angeles, Los Angeles, CA, United States

Abstract The most abundant proteins in vertebrates are collagens; this superfamily of proteins consists of 28 members that share a triple helical motif but are structurally and functionally diverse. The majority of collagens are deposited in the extracellular matrix (ECM) and can be bound by different classes of transmembrane receptors, including integrins, receptor tyrosine kinases such as discoidin domain receptors 1 and 2 (DDR1 and DDR2), glycoprotein VI, and the leukocyte-associated immunoglobulin-like receptor-1. Tumors develop and progress in the context of an ECM that is rich in collagens. Furthermore, collagen signaling in tumors contributes to tumor progression, metastasis, and resistance to chemotherapy. DDRs in particular are implicated in regulating tumor cell proliferation, migration, adhesion, and response to growth factors, and in promoting chemoresistance. As such, DDR inhibitors have been developed by different groups in an effort to inhibit collagen-mediated chemoresistance. This chapter provides an overview of the contribution of collagen and collagen signaling to tissue integrity and tumor progression and describes recent strategies to block collagen signaling to enhance chemosensitivity.

Abbreviations α-SMA

alpha smooth muscle actin

AML Bcr-Abl BMP-2 Csk DDR1 DDR2 ECM EGF EMT FACITs FGF GPVI

acute myelogenous leukemia breakpoint cluster region-Abelson kinase bone morphogenetic protein 2 c-src tyrosine kinase discoidin domain receptors 1 discoidin domain receptors 2 extracellular matrix epidermal growth factor epithelial-mesenchymal transition fibril-associated collagens with interrupted triple helices fibroblast growth factor glycoprotein VI

Protein Kinase Inhibitors as Sensitizing Agents for Chemotherapy https://doi.org/10.1016/B978-0-12-816435-8.00007-9

89

# 2019 Elsevier Inc. All rights reserved.

90 HGF IGF-I IGF-II JM LAIR-1 MTD NSCLC p130CAS PDA PDGF PEAK1 PIK3C2A PLCL2 PSCs Pyk2 RTKs Runx2 SCC Shc1 SPARC SQCLC TGF-β TKIs TM VEGF

7. COLLAGEN SIGNALING IN CANCER

hepatocyte growth factor insulin-like growth factor-I insulin-like growth factor-II juxtamembrane leukocyte-associated immunoglobulin-like receptor-1 maximum-tolerated dose nonsmall-cell lung cancer p130 Crk-associated substrate pancreatic ductal adenocarcinoma platelet-derived growth factor pseudopodium-enriched atypical kinase 1 phosphatidylinositol-4-phosphate 3-kinase phospholipase C-like 2 pancreatic stellate cells proline-rich tyrosine kinase 2 receptor tyrosine kinases runt-related transcription factor 2 squamous cell carcinoma src homology and collagen homology 1 secreted protein acidic and rich in cysteine squamous cell lung carcinoma transforming growth factor beta tyrosine kinase inhibitors transmembrane vascular endothelial growth factor

Conflict of Interest No potential conflicts of interest were disclosed.

INTRODUCTION The extracellular matrix (ECM) is the major noncellular compartment of the tumor microenvironment and is recognized to have important functions in cancer progression [1]. The ECM is not a static structure that simply maintains tissue morphology; it is a dynamically regulated network that directly interacts with cancer cells and stromal cells in tumors [2]. Major components of the ECM include collagens, fibronectin, and laminin, which are mainly produced by tissue fibroblasts [3]. Collagens, of which there are many types, are the most abundant constituent of the ECM in most cancers. Like many other ECM proteins, collagens can mediate specific signaling pathways by binding to cell surface receptors. Integrins function as the major cell receptors for ECM proteins, including collagens [4, 5]. Integrins are heterodimers, comprising α and β subunits. In mammals, there are 18 α subunits and 8 β subunits, generating a total of 24 combinations. They can be classified according to ligand specificity. For example, integrins α1β1 and α2β1 bind GFOGER, an amino peptide sequence contained in collagen I. The ligation of integrins by ECM components induces integrin clustering and the assembly of focal adhesions. Integrins lack detectable enzymatic activity but stimulate downstream signaling through the assembly of focal adhesion, which recruits signaling intermediates. In contrast to integrins, discoidin domain receptors (DDRs) are receptor tyrosine kinases (RTKs) that bind to fibrillar collagens [6]. DDRs are unique RTKs involved in

91

COLLAGEN TYPES

the binding of collagens. In this chapter, we will highlight the collagen signaling pathways mediated by the DDRs, their functions in cancers, and their potential as therapeutic targets.

COLLAGEN TYPES As major components of the ECM, collagens have very important functions under physiological conditions and during tumor progression. There are 28 members in the collagen family, consisting of about 30% of the total protein mass in mammals [7] (Table 1). Collagens are diverse structurally and functionally, with the common structural feature of a triple helix. Physiologically, collagens make up supramolecular structures in which the individual collagen triple helices form higher-order complexes such as fibers or sheet-like configurations. The most common collagen types are the fibrillar collagens (collagen types I–III) and the collagens that form networks (e.g., basement membrane collagen type IV) [7]. The functions of collagens vary, from providing structural support, to mediating cellular interactions, to TABLE 1

List of Collagen Types, Classifications, Locations, and Functions.

Type

Classification

Localization/Function

I

Fibril-forming

Noncartilaginous connective tissues (e.g., tendon, ligament, cornea, bone, annulus fibrosis, skin)

II

Fibril-forming

Cartilage, vitreous humor, and nucleus pulposus

III

Fibril-forming

Codistributes with collagen I, especially in embryonic skin and hollow organs

IV

Network-forming

Basement membranes

V

Fibril-forming

Codistributes with collagen I, especially in embryonic tissues and in cornea

VI

Beaded filamentforming

Widespread, especially in muscle

VII

Anchoring fibrils

Dermal-epidermal junction

VIII

Network-forming

Descement’s membrane

IX

FACIT

Codistributes with collagen II, especially in cartilage and vitreous humor

X

Network-forming

Hypertrophic cartilage

XI

Fibril-forming

Codistributes with collagen II

XII

FACIT

Found with collagen I

XIII

Transmembrane

Neuromuscular junctions, skin

XIV

FACIT

Found with collagen I

XV

Endostatins

Located between collagen fibrils that are close to basement membranes; found in the eye, muscle, and microvessels; a close structural homologue of collagen XVIII

XVI

FACIT

Integrated into collagen fibrils and fibrillin-1 microfibrils

XVII

Transmembrane

Also known as the bullous pemphigoid antigen 2/BP180; localized to epithelia; an epithelial adhesion molecule; ectodomain cleaved by ADAM proteinases Continued

92

7. COLLAGEN SIGNALING IN CANCER

TABLE 1 List of Collagen Types, Classifications, Locations, and Functions.—Cont’d Type

Classification

Localization/Function

XVIII

Endostatins

Associated with basement membranes; endostatin is proteolytically released from the C-terminus of collagen XVIII; important for retinal vasculogenesis

XIX

FACIT

Rare; localized to basement membrane zones; contributes to muscle physiology and differentiation

XX

FACIT

Widespread distribution, most prevalent in corneal epithelium

XXI

FACIT

Widespread distribution

XXII

FACIT

Localized at tissue junctions (e.g., myotendinous junction, cartilagesynovial fluid, hair follicle dermis)

XXIII

Transmembrane

Limited tissue distribution; exists as a transmembrane and shed form

XXIV

Fibril-forming

Shares sequence homology with the fibril-forming collagens; has minor interruptions in the triple helix; selective expression in developing cornea and bone

XXV

Transmembrane

CLAC-P—precursor protein for CLAC (collagenous Alzheimer amyloid plaque component)

XXVI

Beaded filamentforming

Also known as EMI domain-containing protein 2, protein Emu2, Emilin and multimerin domain-containing protein 2

XXVII

Fibril-forming

Shares sequence homology with the fibril-forming collagens; has minor interruptions in the triple helix; found in embryonic cartilage, developing dermis, cornea, inner limiting membrane of the retina, and major arteries of the heart; restricted to cartilage in adults; found in fibrillar-like assemblies

XXVIII

Beaded filamentforming

A component of the basement membrane around Schwann cells; a von Willebrand factor A domain-containing protein with numerous interruptions in the triple helical domain

FACIT, fibril-associated collagens with interrupted triple helices. Modified from Kadler KE, Baldock C, Bella J, Boot-Handford RP. Collagens at a glance. J Cell Sci 2007;120:1955–58.

interacting with other ECM molecules and components, to delineating the physiological structure and characteristics of tissues.

COLLAGEN STRUCTURE All collagen types are characterized by their triple helix, a tight right-handed helix of three α chains [7, 8]. Collagen molecules can assemble as homotrimers or heterotrimers that are comprised of two or three distinguishable α-chain types. In fibril-forming collagens, the α chains are three left-handed polyproline II helices twisted in a right-handed triple helix with a one-residue stagger between adjacent α chains. Each of these α chains contains one or more regions with repeating amino acid motif glycine-X-Y (X and Y can be any amino acid, but frequently are proline and 4-hydroxyproline, respectively). In several collagen types (collagen I, II, III, and V/XI) 3-hydroxiproline residues have also been identified that function in supramolecular assembly formation. Because of the presence of glycine-X-Y imperfections and interruptions, the triple helix, while rod-shaped, can be flexible.

COLLAGENS IN NORMAL PHYSIOLOGY AND TUMORIGENESIS

93

Based on supramolecular assemblies, collagens can be subdivided into fibrils, beaded filaments, anchoring fibrils, and networks subfamilies. Collagen fibrils are made of different collagens in different tissues. For example, in skin, collagen fibrils are comprised of mainly collagens I and III, while in cartilage, collagens II, IX, and XI, or collagens II and III, predominate, and in the cornea, collagens I and V are abundant. Collagen fibril diameter can range from 15 to 500 nm and can also form supertwisted microfibrils that interdigitate with neighboring microfibrils, leading to quasi-hexagonal packing. In contrast to collagens that form fibrils, fibril-associated collagens with interrupted triple helices (FACITs) do not form fibrils directly; however, they are associated with the surface of collagen fibrils. For example, collagens XII and XIV are associated with collagen I-containing fibrils, while collagen IX is closely associated with the surface of cartilage collagen fibrils mainly composed of collagen II. Other major types of collagens form networks. Collagen IV, which is found primarily in the basal lamina, is important for the anchorage of the epithelium to connective tissue. Collagen IV fibers link head-to-head rather than in parallel, thus forming a network. Collagen IV also lacks the regular glycine in every third residue necessary for the tight helix. These two features cause the collagen to form networks instead of fibrils.

COLLAGENS IN NORMAL PHYSIOLOGY AND TUMORIGENESIS The 28 types of collagens are differentially expressed and localized among tissue types and display diverse functions (Table 1). One of their major functions is to maintain the structural integrity of tissues and organs. Collagen fibrils are critical components that provide strength, flexibility, and structural integrity for tissues (i.e., skin, tendon, bone, ligament, cornea, and cartilage) [9]. Besides the biomechanical and structural aspects, under normal physiological conditions, collagens are involved in many additional functions. The collagen network supports cellECM interaction, cell polarity, differentiation, and survival [10, 11]. Most of these functions are mediated through collagen receptors, which we will discuss in detail below. Collagens can also bind to various growth factors and cytokines and regulate growth signaling indirectly. For example, in bone, collagens bind to insulin-like growth factor (IGF)-I and IGF-II [12, 13], and during bone remodeling, degradation of the collagens by osteoclasts releases collagen-bound IGFs to induce new bone formation via the stimulation of osteoblastic activity in a paracrine manner. Besides IGFs, collagens have also been shown to bind to transforming growth factor beta (TGF-β) [14] and bone morphogenetic protein 2 (BMP-2) [15], thus acting as a reservoir of these growth factors within the tissues. During tumor progression, tumor stroma undergoes consistent remodeling, with collagens dynamically degrading, redepositing, cross-linking, and stiffening [2]. As a result, many cancers are characterized by the increased deposition of collagens, including collagens I, III, and IV [16]. The remodeling of collagens has been shown to have a significant impact on cancer cells, including by affecting gene expression, cell proliferation, cell migration, and resistance to therapies [17, 18]. In breast cancer, it has been shown that during intravasation, cancer cells migrate rapidly along collagen fibers [19]. This indicates the direct contribution of collagens in mediating tumor metastasis.

94

7. COLLAGEN SIGNALING IN CANCER

COLLAGEN EXPRESSION IN PANCREATIC DUCTAL ADENOCARCINOMA Pancreatic cancer, one of the most collagen-rich cancers, is a significant health problem with known risk factors such as chronic and hereditary pancreatitis, familial cancer syndromes, cigarette smoking, and late-onset diabetes mellitus [20]. Fully 95% of pancreatic cancers are classified as exocrine tumors, mainly pancreatic ductal adenocarcinoma (PDA), while the other 5% consist of neuroendocrine tumors [21]. According to a study conducted by Rahib and colleagues [22], there were approximately 43,000 new cases and 36,000 deaths of pancreatic cancer in the United States in 2010. Following this trend, a report by the American Cancer Society predicts that there will be about 54,000 new cases (accounting for about 3% of all cancers in both men and women) and an estimated 43,000 deaths (accounting for 7% of mortality in both men and women) for pancreatic cancer in the year 2017. Furthermore, pancreatic cancer is projected to become the second-leading cause of cancer-related deaths in the United States by the year 2030. This disease is one of the most difficult cancers to treat, with a 5-year survival rate of approximately 7%, which has remained largely unchanged over the past 25 years [23]. The majority of PDA patients typically present with locally advanced or metastatic disease, with a median survival of 6–10 months and 3–6 months, respectively [24]. Although 10%–15% of patients have potentially resectable tumors, many patients experience recurrence of disease following surgery [20]. Gemcitabine is the standard chemotherapeutic drug for patients with advanced pancreatic cancer, and a phase-III trial in 1997 demonstrated that it provided a modest survival advantage (median survival 5.6 months) and a reduction of disease-related symptoms [25]. However, the severity of this disease alongside the lack of effective treatment modalities has highlighted the pressing need for improved diagnostic and treatment strategies. A substantial characteristic of PDA is the formation of a dense desmoplastic reaction. This is typically characterized by an abnormal accumulation of fibrotic tissue that is thought to facilitate tumor growth and metastasis [26]. In PDA, the desmoplastic landscape consists of a heterogeneous cell population that includes fibroblasts, pancreatic stellate cells (PSCs), vascular endothelial cells, and immune cells, which in conjunction with the fibrotic network and ECM results in the formation of a complex tumor microenvironment that promotes for PDA development, invasion, metastasis, and resistance to chemotherapy [27]. The epithelial component of PDA typically constitutes only 10%–20% of the tumor volume, and the rest of the tumor is comprised of stromal cells and ECM. The ECM is formed and regulated through the cooperation of various cancer cell-derived growth factors, including TGF-β, epidermal growth factor (EGF), IGF-1, fibroblast growth factor (FGF), and hepatocyte growth factor [27, 28]. As a result of the strong desmoplastic reaction, interstitial connective tissue increases, and this is accompanied by a significant increase of collagen types I, III, IV, and fibronectin and laminin [29, 30]. Compared to the collagen of the normal pancreas, fibrillar collagen in PDA is reorganized and becomes more aligned as the disease progresses [31]. Moreover, collagen alignment correlates with worse outcomes in patients and cancer cell epithelial-mesenchymal transition (EMT). Connective tissue cells in the stroma of PDA have been shown to be the major site of collagen I and III expressions. Further studies indicate that collagens are mainly

COLLAGEN RECEPTORS

95

secreted by PSCs, a specific population of fibroblasts in PDA [30]. Activated PSCs are characterized by the expression of alpha smooth muscle actin (α-SMA), and as a result α-SMA-positive cells often colocalize with collagen. Although stromal cells contribute largely to ECM production, pancreatic cancer cells also produce different components of ECM, including collagens I, III, and IV. In xenograft models with human pancreatic cancer cell lines, collagen I and laminin were found to be most pronounced in well-differentiated tumors [32].

COLLAGEN FUNCTION IN THE PDA The tumor ECM can be a barrier for drugs as it indirectly limits the delivery of chemotherapeutic or other targeted agents through vascular compression [29, 33]. Drug delivery to tumors is dependent on the function of perfused vessels [33–35]. Interstitial fluid pressure is elevated in tumors and in particular in PDA as a result of high cellular content and dense ECM deposition [36, 37]. The interstitial fluid pressure compresses and collapses blood vessels, reducing perfusion [38]. These physiological constraints limit the efficacy of chemotherapy [39]. Moreover, in PDA patients with deficient TGF-β signaling, epithelial STAT3 activity is elevated, which leads to an ECM-enriched stroma that is associated with shorter patient survival times in part due to enhanced epithelial plasticity, which is associated with chemoresistance [40]. Besides contributing to the physical barriers, as one of the most abundant components of the PDA stroma, collagens affect cancer progression directly through signaling and providing building blocks for cell survival [11, 41]. For example, collagen I induces a disruption of E-cadherin and an increase of N-cadherin expression in pancreatic cancer cells [42, 43], leading to cancer cell invasiveness and metastasis. Collagen I can also increase the survival of pancreatic cancer cells treated with 5-fluorouracil by up to 62% [44]. Further, collagen can be a nutrient source for cancer cells. The collagen-rich stroma in pancreatic cancer can be degraded into proline-rich fragments and used as a nutrient source when other fuels are limited [45]. This collagen degradation can be mediated by matrix metalloproteinases (MMPs), a large family of zinc-containing proteolytic enzymes [46]. MMP-2 and MMP-9, which can degrade collagens, are elevated in pancreatic cancer and have been shown to contribute to tumor cell migration, invasion, and tumor cell metabolism [47].

COLLAGEN RECEPTORS Collagens interact with four classes of cell surface receptors—integrins, DDRs, glycoprotein VI (GPVI), and leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) [4, 11, 48, 49]. All of these receptors require collagen to be in its native triple-helical structure [50]. GPVI is a platelet-specific membrane glycoprotein that has an important function in the collageninduced activation and aggregation of platelets. LAIR-1 is an inhibitory receptor found mainly on immune cells, such as NK cells, T cells, and B cells. It inhibits immune responses upon activation to prevent lysis of cells recognized as self. Integrins and DDRs are the major collagen receptors involved in tumor progression. Integrins have been discussed in detail by

96

7. COLLAGEN SIGNALING IN CANCER

many groups [51–53]; below we will elaborate on the function and contribution of DDRs to cancer progression.

DDRs DDRs are type-I transmembrane (RTKs) characterized by an N-terminal extracellular discoidin domain containing a collagen-binding site [6]. The discoidin domain is termed as such based on its homology to lectin discoidin I, a protein secreted by the slime mold dictyostelium discoideum [54]. There are two types of DDRs—DDR1 and DDR2 [11]. The DDRs are widely and differentially expressed among tissue types throughout development. DDR1 is normally expressed in epithelial cells, with relatively high expression in the pancreas, brain, lung, kidney, spleen, and placenta, while DDR2 is expressed in mesenchymal cells, with high expression in skeletal and heart muscle, and the kidney and lung. Both DDRs are expressed throughout the development of the nervous system. While the DDRs are important for physiological development, their tissue-specific functions are not fully understood. The collagen-binding sites within the discoidin domains are highly conserved and DDRs can be activated by many different types of collagen [6, 54, 55]. DDRs all recognize the GVMGVO (O, hydroxyproline) motif within fibrillar collagens I–III and V. In addition, DDR1 and DDR2 also have their own binding specificity, with DDR1 only binding to collagen IV, and DDR2 only binding to collagen X. Since DDR-binding sites on collagens are distinct from integrin-binding sites, the simultaneous activation of DDRs and integrins is possible, both of which contribute to upregulation of N-cadherin in pancreatic cancer [43]. Although the structures of DDRs are similar to many other RTKs, they are unique among RTKs because they have unusually slow kinetics of activation. After binding to collagen, DDRs can be autophosphorylated on tyrosine residues but full activation can require 4 h and activity can persist up to 18 h. The extracellular discoidin domain is followed by an extracellular juxtamembrane (JM) membrane region, then a single transmembrane domain and an unusually large cytosolic JM domain which contains phosphorylatable tyrosines may serve as docking sites for many signaling intermediates [11]. A catalytic kinase domain follows the cytosolic JM domain and at the very end comes a short C-terminal tail. There are five different isoforms of DDR1 (a–e) generated through alternative splicing. The isoforms termed DDR1a and DDR1b are the most widely distributed, while the others are less common. DDR1a lacks a 37-residue segment present in the cytosolic JM region of DDR1b. This segment contains important phosphorylation sites. In the shorter DDR1a isoform, two tyrosines (Y513 and Y520) are missing. After phosphorylation, these tyrosines are reported to bind Src homology and collagen homology 1 (Shc1) and c-src tyrosine kinase, respectively [56, 57]. Once DDR1 is activated by collagens, it stimulates downstream effectors, including proline-rich tyrosine kinase 2 (Pyk2), which belongs to the same family and is very similar to FAK [43]. The activation of Pyk2 induced by DDR1 is mediated by the adaptor protein Shc1 that binds to phosphorylated site Y513 of DDR1b [58]. Then Pyk2 activates a downstream scaffold protein called p130 Crk-associated substrate (p130CAS). As a result,

DDRs

97

p130CAS activation leads to a Rap1-MLK3-MKK7-JNK1-cJun cascade and induces a series of biological changes in cancer cells, including cell scattering, and making the cells more mesenchymal and chemoresistant. We also found that pseudopodium-enriched atypical kinase 1 (PEAK1) is involved in the DDR1 signaling pathway, which has been shown to be a tumorigenic effector in colon and pancreatic cancers [59–61]. However, it is unclear if and how PEAK1 interacts with other signaling proteins in the pathway. Moreover, Src has also been shown to be involved in the pathway [62], and DDR1 signaling also crosstalks with other important prosurvival pathways of cancer cells, such as the Notch signaling pathway [63] and Hippo signaling pathway [64]. Compared to DDR1, the intracellular signaling pathway of DDR2 is undefined, although several potential downstream effectors of DDR2 signaling have been identified through phosphoproteomic analysis [65]. These include SHP-2, NCK1, the SRC family kinase LYN, phospholipase C-like 2, and phosphatidylinositol-4-phosphate 3-kinase (PIK3C2A); additional validation is needed to verify these candidate effectors. DDR1 and DDR2 are functionally important in normal as well as pathological development. In normal conditions, DDR1 is important in organogenesis and DDR2 in bone growth [11]. Ddr1 knockout mice are phenotypically characterized by small stature and genderspecific phenotypes [66]. Females display multiple reproductive defects, including impaired blastocyst implantation; therefore, a large percentage of Ddr1
/
females are infertile. As Ddr1 is expressed throughout all stages of mammary development, the most significant Ddr1
/
defect is abnormal branch formation of the mammary gland, which results in failed milk secretion and the inability to nourish pups. The mammary glands in pregnant Ddr1
/
mice present an altered alveolar structure, with the fat pad filled with ducts. In Ddr1
/
female mice, ductal development in the mammary glands is delayed in puberty, which results in an altered formation of the terminal end bunds and secondary branching. Ddr1
/
mice also display progressive morphological alterations and severely decreased auditory function due to defective inner ear development [67]. Under pathological conditions, DDR1 has been shown to function in inflammation or fibrotic diseases. In a model of bleomycin-induced lung fibrosis, a widely used mouse model for human idiopathic pulmonary fibrosis, Ddr1
/
mice were largely protected from lung injury and fibrosis [68]. The profibrotic and proinflammatory functions of DDR1 were also demonstrated in mouse models of kidney injury [69]. DDR1 expression is elevated in patients with fibrotic diseases, lupus nephritis, and Goodpasture’s syndrome, as well as in a mouse model of crescentic glomerulonephritis [70]. Moreover, Alport mice, a model of chronic kidney fibrosis, crossed with the Ddr1
/
mice have reduced renal fibrosis and inflammation [71]. All these indicate that DDR1 might be a potential therapeutic target in fibrotic or inflammatory diseases. Ddr2-deficient mice exhibit a characteristic phenotype of dwarfism with short long bones and a short snout, due to reduced chondrocyte proliferation [72]. These mice, termed slie or smallie, are sterile in addition to their dwarfism: slie females are anovulatory and slie males lack spermatogenesis [73]. Ddr2 is a key regulator throughout bone growth as it participates in endochondrial ossification through the regulation of chondrocyte maturation [74]. Ddr2 also regulates intramembranous ossification through the regulation of osteoblast differentiation via the phosphorylation of runt-related transcription factor 2, a master transcription

98

7. COLLAGEN SIGNALING IN CANCER

factor in skeletal development [74, 75]. In osteoblasts, Ddr2-collagen interactions mediate the secretion of lysyl oxidase [76], an enzyme that catalyzes the cross-linking of collagen fibers essential for bone strength.

REGULATION OF DDR1 SIGNALING BY SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE We have shown that another ECM protein, secreted protein acidic and rich in cysteine (SPARC), competes with DDRs for binding to collagen and reduces collagen-induced DDR signaling. SPARC, also known as osteonectin [77] or BM-40 [78], is a 303 amino acid (human) or 302 amino acid (mouse) glycoprotein approximately 35 kDa in size [79]. It is a matricellular protein that is secreted into the ECM where it regulates angiogenesis, cell adhesion, cell migration, cell proliferation, cell survival, and tissue remodeling during wound healing [80, 81]. SPARC interacts with, or indirectly regulates, a variety of growth factors, including FGF, TGF, vascular endothelial growth factor (VEGF), and platelet-derived growth factor [82–85]. The expression of SPARC during mammalian development and tissue differentiation is robust, but it declines in the majority of organs after maturation [86]. Ultimately, the expression of SPARC is limited postdevelopment to tissues with high ECM turnover, such as bone and gut epithelia. However, SPARC is induced during wound healing, at sites of angiogenesis, and during tumorigenesis [87–89]. SPARC functions as a mediator of tissue remodeling in that it binds directly to fibrillar collagens I, III, and V, and to basement membrane collagen IV [90, 91]. Our lab, and others, have previously demonstrated that tumors grown in Sparc
/
animals are more aggressive and exhibited a diminished deposition of ECM compared with those grown in wild-type (Sparc+/+) counterparts [92, 93]. Additionally, in an orthotopic model of PDA in Sparc+/+ and Sparc
/
mice, tumors grown in the absence of host-derived SPARC showed a marked reduction in the deposition of fibrillar collagens I and III, basement membrane collagen IV, and the collagen-associated proteoglycan decorin [94]. Although there are discrepancies throughout the literature, it has been largely accepted that SPARC overexpression is associated with oncogenesis in breast cancer, prostate cancer, melanoma, meningioma, gastric carcinoma, head and neck cancer, and glioma [95]. SPARC is a critical tumor-secreted permeability factor and a novel paracrine mediator of endothelium permeability during melanoma’s metastatic dissemination to lungs [96]. Conversely, SPARC expression has been implicated as a tumor suppressor in a variety of tumors, including pancreatic, lung, renal, esophageal, hepatocellular, uterine, colorectal, ovarian, neuroblastoma, and acute myelogenous leukemia. In fact, SPARC is considered a therapeutic target when tumor cells overexpress it, but a therapeutic agent when tumor cells underexpress it. The underexpression or loss of SPARC occurs throughout many cancer types. For instance, the SPARC promoter is commonly hypermethylated in PDA cell lines and xenograft tumors [97], ovarian cancer cell lines [98], primary colorectal cancer specimens and cell lines [99], and multiple myeloma patient samples and cell lines [100]. Additionally, among endometrioid ovarian carcinomas, frequent epigenetic inactivation of SPARC was noted in the development of nonserous ovarian carcinomas of Lynch and sporadic origin [101].

DDR AS A THERAPEUTIC TARGET

99

Our lab has previously demonstrated that in an orthotopic model of PDA Sparc
/
mice exhibited a significant increase in metastasis compared with Sparc+/+ controls [94]. These findings indicated that SPARC is critical to the host response to tumorigenesis and that the loss of SPARC expression accelerates tumor progression. A subsequent study by Von Hoff and colleagues [102] demonstrated the function of SPARC in the modulation of patient response to therapy. Patients were treated with the maximum-tolerated dose (MTD) of gemcitabine (1000 mg/m2) plus nab-paclitaxel (125 mg/m2) weekly for 3 weeks, repeated every 4 weeks. Overall survival was 12.2 months with a 1-year survival of 48%. These findings were among the highest reported for a phase-II study in patients with PDA. Along with this, high stromal SPARC expression was correlated with a significant increase in patient survival. Altogether these observations indicated that stromal SPARC expression may be an important biomarker for the efficacy of gemcitabine plus nab-paclitaxel combination regimens in PDA. Structural studies indicate that SPARC and DDRs bind to the same epitope (GVMGFO) on fibrillar collagens [103, 104]. Collagen is associated preferentially with cell surfaces instead of being deposited into the ECM in the absence of SPARC. Our lab found that SPARC inhibits collagen I from binding to Ddr1 [103]. Further, in the PDA tumors grown in Sparc
/
mice, the activation of DDR1 as well as its downstream signaling proteins Pyk2 and PEAK1 were elevated compared to tumors in Sparc+/+ animals, correlating with decreased survival and increased metastasis in the absence of SPARC. These results highlight that DDR1 signaling contributes to PDA progression, and the beneficial effects of SPARC in pancreatic cancer may be due to its inhibition of DDR1 function during tumor progression.

DDR AS A THERAPEUTIC TARGET DDR1-mediated cell adhesion to collagen is essential for tissue and cellular functions in normal and pathological processes. In pancreatic tumor tissues, DDR1 was identified as one of the 72 genes that were significantly upregulated in malignant versus benign pancreatic tumors [105]. High levels of DDR1 mRNA were found in hepatocellular carcinomas, which significantly correlated with advanced tumor stage [106]. A study on nonsmall-cell lung cancer (NSCLC) indicated that DDR1 expression increased and contributed to the progression of this disease [107], and a study evaluating a cohort of 83 patients with NSCLC found that tumors with high DDR1 protein levels were associated with poor survival [108]. Ford and colleagues [109], using 146 primary NSCLC and an independent set of 23 matched tumors and normal lung tissue samples, showed that DDR1 mRNA was upregulated in tumors versus normal tissues. Another study evaluating 171 NSCLC samples showed that DDR1 expression was associated with lymph node metastasis and poor overall survival [110]. DDR1 was also highly expressed in high-grade pediatric [111] and adult brain tumors [112], and significantly correlated with poor clinical outcome [113]. Moreover, DDR1 has been associated with resistance to chemotherapy and can mediate prosurvival signals in breast cancer and lymphoma cell lines [114, 115] and may be involved in the recurrence of certain types of cancer [116]. Likewise, downregulation of DDR1 expression significantly enhanced the chemosensitivity of breast cancer cells to genotoxic drugs [117]. Moreover, the combined inhibition of DDR1 and Notch signaling has shown significant efficacy for KRAS-mutant lung adenocarcinoma [63]. In a recent study, we found that the inhibition of DDR1 had striking efficacy in

100

7. COLLAGEN SIGNALING IN CANCER

combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors, reducing primary tumor burden, and significantly improving chemoresponse [59]. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcomes for pancreatic cancer patients. DDR2 was recently shown to be a key regulator of metastasis and invasion for breast cancer cells [118]. Zhang and colleagues have reported that DDR2 is expressed in 71% of invasive ductal breast cancer and that 5% of the invasive breast tumors had an amplified DDR2 copy number, associated with a worse survival rate. DDR2 enhanced invasion, migration, and metastasis of breast cancer cells as it regulated and stabilized Snail1 protein levels and activity through Src-dependent stimulation of Erk1 activity [118, 119]. DDR2 expression in human breast epithelial cells has been associated with an induction of EMT [120]. Moreover, DDR2 has been identified as a potential RTK target for the treatment of breast cancer metastasis [118]. Microarray analyses in aneuploid papillary thyroid carcinomas revealed that DDR2 was one of the few genes that were highly expressed in patients with metastatic disease at the time of diagnosis [121]. Moreover, in the same study, an analysis of tumors from patients who had died from this disease revealed that DDR2 was one of the most overexpressed genes as well. In addition, genetic alterations of DDR2 have been linked to different forms of diseases such as NSCLC and squamous cell lung carcinoma [122–124]. Consistent with a protumorigenic action of DDR2, Ddr2
/
mice display reduced primary tumor-associated angiogenesis and reduced lung colonization following tail vein injection [125]. Wild-type and Ddr2
/
-mutant mice were implanted subcutaneously with three types of syngeneic tumor cells—B16-F10 melanoma, H22 hepatic carcinoma, and S180 sarcoma. Tumor growth in Ddr2
/
mice was slow compared with that in control mice, which led to an approximately fivefold difference in tumor volume at the end of the study. In aggregate, these studies indicate that DDR1 and DDR2 are potential therapeutic targets for many different types of cancers.

DDR INHIBITORS As promising therapeutic targets, drugs that can target DDRs have been the focus of research efforts. Approaches to targeting the tyrosine kinase activity of DDR1 and DDR2 have included the utility of small-molecule inhibitors designed to disrupt the intracellular kinase activity. Small-molecule tyrosine kinase inhibitors are generally ATP-competitive inhibitors, which bind to either the active (type-I inhibitors) or inactive (type-II and type-III inhibitors) conformation of the kinase, thereby interfering with the transfer of the terminal phosphate of ATP to proteins that contain a tyrosine residue [126, 127]. Type-IV inhibitors are likewise useful for kinase modulation because they allosterically impair kinase activity by binding at sites outside of the ATP-binding cleft [128, 129]. However, type-II and especially type-III inhibitors, or those that stabilize catalytically inactive states, are particularly useful in drug development initiatives. Several small-molecule inhibitors that were originally developed to target the activity of the breakpoint cluster region-Abelson kinase (Bcr-Abl) for use in myelogenous leukemia, namely imatinib (also known as STI-571 or Gleevec), dasatinib, nilotinib, and bafetinib (also known as INNO-406), also potently inhibit DDR activity [130, 131]. Imatinib and nilotinib are

CONCLUSION

101

type-II inhibitors that bind to and stabilize an inactive kinase form that is characterized by “DFG-out” conformation [132]. The DFG-out motif opens an additional cavity, a hydrophobic allosteric site that, in addition to the ATP binding pocket, is targeted by type-II inhibitors. Other type-II Bcr-Abl inhibitors such as bafetinib have also displayed strong DDR inhibition [133]. Dasatinib is a type-I inhibitor that targets kinase domains in the active form and is characterized by an open conformation of the activation loop. Dasatinib in particular has demonstrated promising therapeutic efficacy in lung cancer cells harboring gain-of-function mutations of DDR2 [134], as well as in two squamous cell carcinoma (SCC) patients with a DDR2S768R mutation who had significant shrinkage of their tumors after dasatinib treatment [135]. Recently, Gao et al. [136] reported on a pyrazolopyrimidine alkyne derivative of the previously described DDR1 inhibitors, which displayed a potently specific IC50 for DDR1 over DDR2. This is therapeutically attractive, as a DDR1-specific inhibitor was not previously available. On the basis of the sequence similarity of DDR1, DDR2, and Bcr-Abl in the kinase domain, Gao et al. conducted a focused screening against an internal library containing approximately 2000 kinase inhibitors and identified N-isopropyl-4-methyl-3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl) 7rh benzamide (7rh) as a new potent DDR1 inhibitor. The compound inhibits DDR1 with an IC50 value of 6.8 nM and is significantly less active against DDR2 and Bcr-Abl, with IC50 values of 101.4 and 355 nM, respectively. The detailed interaction of the 7rh compound with DDR1 remains unclear, though it is predicted that the compound binds to the receptor with a type-II-binding mode [137]. Cell-based investigation has demonstrated that 7rh inhibits the activation of DDR1 and downstream signaling in a concentration-dependent manner and potently suppresses the proliferation, invasion, adhesion, and tumorigenicity of cancer cells. The 7rh compound is therapeutically attractive as preliminary pharmacokinetic studies in rats have demonstrated that the compound possesses a promising pharmacokinetic profile with an oral bioavailability of 67.4% and T1/2 of 15.5 h when dosed at 25 mg/kg by oral gavage. Recent studies, including ours, have proved that 7rh works effectively in vivo in preclinical models of pancreatic, gastric, and lung cancer. The function of DDR2 in tumor progression has indicated the need for the identification of potent DDR2 inhibitors. There is only limited understanding of pharmacological interactions of DDR2 inhibition. Recently, Richters and colleagues [138] discovered novel DDR2-specific type-II and type-III small-molecule inhibitors. The IC50 for two compounds in cell-free kinase assays reported for DDR2 versus DDR1 were 75 and 18 nM compared to 235 and 39 nM, respectively. Furthermore, these compounds may be therapeutically attractive in targeting DDR2 in breast cancer patients or in SCC patients with the DDR2S768R mutation, as suggested by dasatinib treatment.

CONCLUSION The collagen-rich tumor microenvironment is now recognized to be a hallmark feature of many different types of cancers. Preclinical and clinical data demonstrate that collagen and its signaling promotes cancer progression. New drugs are available to target DDRs and hold significant potential in reducing chemoresistance. However, there are still many questions regarding the biology of DDRs in cancer. For example, what is the contribution of DDRs

102

7. COLLAGEN SIGNALING IN CANCER

to tumor growth and metastasis in different cancer types? What is the protein interactome that regulates DDR activity in cancer cells? Additionally, the signaling pathways activated by DDRs wait for further definition. The availability of novel and selective inhibitors of DDR1 and DDR2 provides the opportunity to address many of these questions in relevant and robust models. We anticipate that as these new inhibitors are more completely characterized, they will enter clinical testing in cancer patients where they have the potential to augment the efficacy of standard or targeted therapy.

Acknowledgment This work is supported in part by the NIH (R01CA192381 and U54 CA210181 Project 2 to Rolf Brekken) and the Effie Marie Cain Scholarship in Angiogenesis Research. We thank Dave Primm for editorial support.

References [1] Venning FA, Wullkopf L, Erler JT. Targeting ECM disrupts cancer progression. Front Oncol 2015;5:224. [2] Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 2014;15:786–801. [3] Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci 2010;123:4195–200. [4] Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002;110:673–87. [5] Rathinam R, Alahari SK. Important role of integrins in the cancer biology. Cancer Metastasis Rev 2010;29:223–37. [6] Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997;1:13–23. [7] Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol 2011;3:a004978. [8] Kadler KE, Baldock C, Bella J, Boot-Handford RP. Collagens at a glance. J Cell Sci 2007;120:1955–8. [9] Wess TJ. Collagen fibril form and function. Adv Protein Chem 2005;70:341–74. [10] Schor SL. Cell proliferation and migration on collagen substrata in vitro. J Cell Sci 1980;41:159–75. [11] Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev 2012;31:295–321. [12] Conover CA, Khosla S. Role of extracellular matrix in insulin-like growth factor (IGF) binding protein-2 regulation of IGF-II action in normal human osteoblasts. Growth Horm IGF Res 2003;13:328–35. [13] Jones JI, Gockerman A, Busby Jr. WH, Camacho-Hubner C, Clemmons DR. Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I. J Cell Biol 1993;121:679–87. [14] Paralkar VM, Vukicevic S, Reddi AH. Transforming growth factor beta type 1 binds to collagen IV of basement membrane matrix: implications for development. Dev Biol 1991;143:303–8. [15] Sieron AL, Louneva N, Fertala A. Site-specific interaction of bone morphogenetic protein 2 with procollagen II. Cytokine 2002;18:214–21. [16] Fang M, Yuan J, Peng C, Li Y. Collagen as a double-edged sword in tumor progression. Tumour Biol 2014;35:2871–82. [17] Clark AG, Vignjevic DM. Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol 2015;36:13–22. [18] Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep 2014;15:1243–53. [19] Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER, Segall JE, Pollard JW, Condeelis J. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 2007;67:2649–56. [20] Wong HH, Lemoine NR. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol 2009;6:412–22. [21] Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer 2002;2:897–909. [22] Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–21.

REFERENCES

103

[23] Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, Mariotto A, Lake AJ, Wilson R, Sherman RL, et al. Annual report to the nation on the status of cancer, 1975–2014 featuring survival. J Natl Cancer Inst 2017; 109(9):1–22. [24] Pancreatric Section, B.S.o.G., Pancreatic Society of Great, B., Ireland, Association of Upper Gastrointestinal Surgeons of Great, B., Ireland, Royal College of, P., and Special Interest Group for Gastro-Intestinal, R. Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas. Gut 2005;54(Suppl 5):v1–16. [25] Burris 3rd HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–13. [26] Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther 2007;6:1186–97. [27] Liu H, Ma Q, Xu Q, Lei J, Li X, Wang Z, Wu E. Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer. Curr Pharm Des 2012;18:2395–403. [28] Lane TF, Iruela-Arispe ML, Sage EH. Regulation of gene expression by SPARC during angiogenesis in vitro. Changes in fibronectin, thrombospondin-1, and plasminogen activator inhibitor-1. J Biol Chem 1992;267:16736–45. [29] Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, Lolkema MP, Buchholz M, Olive KP, Gress TM, et al. Stromal biology and therapy in pancreatic cancer. Gut 2011;60:861–8. [30] Phillips P. Pancreatic stellate cells and fibrosis. In: Grippo PJ, Munshi HG, editors. Pancreatic cancer and tumor microenvironment. Trivandrum, India: Transworld Research Network; 2012 [Chapter 3]. [31] Drifka CR, Loeffler AG, Mathewson K, Keikhosravi A, Eickhoff JC, Liu Y, Weber SM, Kao WJ, Eliceiri KW. Highly aligned stromal collagen is a negative prognostic factor following pancreatic ductal adenocarcinoma resection. Oncotarget 2016;7:76197–213. [32] Lohr M, Trautmann B, Gottler M, Peters S, Zauner I, Maillet B, Kloppel G. Human ductal adenocarcinomas of the pancreas express extracellular matrix proteins. Br J Cancer 1994;69:144–51. [33] Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 2013;4:2516. [34] Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 2013;31:2205–18. [35] Tsai AG, Johnson PC, Intaglietta M. Oxygen gradients in the microcirculation. Physiol Rev 2003;83:933–63. [36] Stylianopoulos T, Martin JD, Chauhan VP, Jain SR, Diop-Frimpong B, Bardeesy N, Smith BL, Ferrone CR, Hornicek FJ, Boucher Y, et al. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc Natl Acad Sci U S A 2012;109:15101–8. [37] Stylianopoulos T, Martin JD, Snuderl M, Mpekris F, Jain SR, Jain RK. Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. Cancer Res 2013;73:3833–41. [38] Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK. Pathology: cancer cells compress intratumour vessels. Nature 2004;427:695. [39] Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, Ancukiewicz M, Wang M, Wen PY, Ivy P, Batchelor TT, et al. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 2012;72:402–7. [40] Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE, Barrett AS, Hill RC, Lakins JN, Schlaepfer DD, Mouw JK, et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 2016;22:497–505. [41] Yeh YC, Lin HH, Tang MJ. A tale of two collagen receptors, integrin beta1 and discoidin domain receptor 1, in epithelial cell differentiation. Am J Physiol Cell Physiol 2012;303:C1207–17. [42] Koenig A, Mueller C, Hasel C, Adler G, Menke A. Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. Cancer Res 2006;66:4662–71. [43] Shintani Y, Fukumoto Y, Chaika N, Svoboda R, Wheelock MJ, Johnson KR. Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1. J Cell Biol 2008;180:1277–89. [44] Armstrong T, Packham G, Murphy LB, Bateman AC, Conti JA, Fine DR, Johnson CD, Benyon RC, Iredale JP. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res 2004;10:7427–37.

104

7. COLLAGEN SIGNALING IN CANCER

[45] Olivares O, Mayers JR, Gouirand V, Torrence ME, Gicquel T, Borge L, Lac S, Roques J, Lavaut MN, Berthezene P, et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat Commun 2017;8:16031. [46] Van Doren SR. Matrix metalloproteinase interactions with collagen and elastin. Matrix Biol 2015;44–6: 224–31. [47] Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001;93:178–93. [48] Kehrel B, Wierwille S, Clemetson KJ, Anders O, Steiner M, Knight CG, Farndale RW, Okuma M, Barnes MJ. Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not. Blood 1998;91:491–9. [49] Meyaard L. The inhibitory collagen receptor LAIR-1 (CD305). J Leukoc Biol 2008;83:799–803. [50] Leitinger B. Transmembrane collagen receptors. Annu Rev Cell Dev Biol 2011;27:265–90. [51] Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010;10:9–22. [52] Huang H, Du W, Brekken RA. Extracellular matrix induction of intracellular reactive oxygen species. Antioxid Redox Signal 2017;27:774–84. [53] Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol 2015;25:234–40. [54] Vogel W. Discoidin domain receptors: structural relations and functional implications. FASEB J 1999;13(Suppl): S77–82. [55] Leitinger B. Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2. J Biol Chem 2003;278:16761–9. [56] Lemeer S, Bluwstein A, Wu Z, Leberfinger J, Muller K, Kramer K, Kuster B. Phosphotyrosine mediated protein interactions of the discoidin domain receptor 1. J Proteomics 2012;75:3465–77. [57] Yang G, Li Q, Ren S, Lu X, Fang L, Zhou W, Zhang F, Xu F, Zhang Z, Zeng R, et al. Proteomic, functional and motif-based analysis of C-terminal Src kinase-interacting proteins. Proteomics 2009;9:4944–61. [58] Huang H, Svoboda RA, Lazenby AJ, Saowapa J, Chaika N, Ding K, Wheelock MJ, Johnson KR. Up-regulation of N-cadherin by collagen I-activated discoidin domain receptor 1 in pancreatic cancer requires the adaptor molecule Shc1. J Biol Chem 2016;291:23208–23. [59] Aguilera KY, Huang H, Du W, Hagopian MM, Wang Z, Hinz S, Hwang TH, Wang H, Fleming JB, Castrillon DH, et al. Inhibition of discoidin domain receptor 1 reduces collagen-mediated tumorigenicity in pancreatic ductal adenocarcinoma. Mol Cancer Ther 2017;16:2473–85. [60] Kelber JA, Klemke RL. PEAK1, a novel kinase target in the fight against cancer. Oncotarget 2010;1:219–23. [61] Kelber JA, Reno T, Kaushal S, Metildi C, Wright T, Stoletov K, Weems JM, Park FD, Mose E, Wang Y, et al. KRas induces a Src/PEAK1/ErbB2 kinase amplification loop that drives metastatic growth and therapy resistance in pancreatic cancer. Cancer Res 2012;72:2554–64. [62] Lu KK, Trcka D, Bendeck MP. Collagen stimulates discoidin domain receptor 1-mediated migration of smooth muscle cells through Src. Cardiovasc Pathol 2011;20:71–6. [63] Ambrogio C, Gomez-Lopez G, Falcone M, Vidal A, Nadal E, Crosetto N, Blasco RB, Fernandez-Marcos PJ, Sanchez-Cespedes M, Ren X, et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat Med 2016;22:270–7. [64] Hilton HN, Stanford PM, Harris J, Oakes SR, Kaplan W, Daly RJ, Ormandy CJ. KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling. Biochim Biophys Acta 2008;1783: 383–93. [65] Iwai LK, Chang F, Huang PH. Phosphoproteomic analysis identifies insulin enhancement of discoidin domain receptor 2 phosphorylation. Cell Adh Migr 2013;7:161–4. [66] Vogel WF, Aszodi A, Alves F, Pawson T. Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development. Mol Cell Biol 2001;21:2906–17. [67] Meyer zum Gottesberge AM, Gross O, Becker-Lendzian U, Massing T, Vogel WF. Inner ear defects and hearing loss in mice lacking the collagen receptor DDR1. Lab Invest 2008;88:27–37. [68] Avivi-Green C, Singal M, Vogel WF. Discoidin domain receptor 1-deficient mice are resistant to bleomycininduced lung fibrosis. Am J Respir Crit Care Med 2006;174:420–7.

REFERENCES

105

[69] Guerrot D, Kerroch M, Placier S, Vandermeersch S, Trivin C, Mael-Ainin M, Chatziantoniou C, Dussaule JC. Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy. Am J Pathol 2011;179:83–91. [70] Kerroch M, Guerrot D, Vandermeersch S, Placier S, Mesnard L, Jouanneau C, Rondeau E, Ronco P, Boffa JJ, Chatziantoniou C, et al. Genetic inhibition of discoidin domain receptor 1 protects mice against crescentic glomerulonephritis. FASEB J 2012;26:4079–91. [71] Gross O, Girgert R, Beirowski B, Kretzler M, Kang HG, Kruegel J, Miosge N, Busse AC, Segerer S, Vogel WF, et al. Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease. Matrix Biol 2010;29:346–56. [72] Labrador JP, Azcoitia V, Tuckermann J, Lin C, Olaso E, Manes S, Bruckner K, Goergen JL, Lemke G, Yancopoulos G, et al. The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep 2001;2:446–52. [73] Kano K, Marin de Evsikova C, Young J, Wnek C, Maddatu TP, Nishina PM, Naggert JK. A novel dwarfism with gonadal dysfunction due to loss-of-function allele of the collagen receptor gene, Ddr2, in the mouse. Mol Endocrinol 2008;22:1866–80. [74] Zhang Y, Su J, Yu J, Bu X, Ren T, Liu X, Yao L. An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation. J Bone Miner Res 2011;26:604–17. [75] Lin KL, Chou CH, Hsieh SC, Hwa SY, Lee MT, Wang FF. Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation. J Bone Miner Res 2010;25:2489–503. [76] Khosravi R, Sodek KL, Faibish M, Trackman PC. Collagen advanced glycation inhibits its Discoidin Domain Receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts. Bone 2014;58:33–41. [77] Termine JD, Kleinman HK, Whitson SW, Conn KM, McGarvey ML, Martin GR. Osteonectin, a bone-specific protein linking mineral to collagen. Cell 1981;26:99–105. [78] Mann K, Deutzmann R, Paulsson M, Timpl R. Solubilization of protein BM-40 from a basement membrane tumor with chelating agents and evidence for its identity with osteonectin and SPARC. FEBS Lett 1987;218:167–72. [79] Sage H, Johnson C, Bornstein P. Characterization of a novel serum albumin-binding glycoprotein secreted by endothelial cells in culture. J Biol Chem 1984;259:3993–4007. [80] Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 2002;14:608–16. [81] Brekken RA, Sage EH. SPARC, a matricellular protein: at the crossroads of cell-matrix. Matrix Biol 2000;19:569–80. [82] Francki A, McClure TD, Brekken RA, Motamed K, Murri C, Wang T, Sage EH. SPARC regulates TGF-beta1dependent signaling in primary glomerular mesangial cells. J Cell Biochem 2004;91:915–25. [83] Hasselaar P, Sage EH. SPARC antagonizes the effect of basic fibroblast growth factor on the migration of bovine aortic endothelial cells. J Cell Biochem 1992;49:272–83. [84] Kupprion C, Motamed K, Sage EH. SPARC (BM-40, osteonectin) inhibits the mitogenic effect of vascular endothelial growth factor on microvascular endothelial cells. J Biol Chem 1998;273:29635–40. [85] Raines EW, Lane TF, Iruela-Arispe ML, Ross R, Sage EH. The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors. Proc Natl Acad Sci U S A 1992;89:1281–5. [86] Bradshaw AD, Sage EH. SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury. J Clin Invest 2001;107:1049–54. [87] Mendis DB, Ivy GO, Brown IR. SPARC/osteonectin mRNA is induced in blood vessels following injury to the adult rat cerebral cortex. Neurochem Res 1998;23:1117–23. [88] Pen A, Moreno MJ, Martin J, Stanimirovic DB. Molecular markers of extracellular matrix remodeling in glioblastoma vessels: microarray study of laser-captured glioblastoma vessels. Glia 2007;55:559–72. [89] Reed MJ, Puolakkainen P, Lane TF, Dickerson D, Bornstein P, Sage EH. Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization. J Histochem Cytochem 1993;41:1467–77. [90] Sage H, Vernon RB, Funk SE, Everitt EA, Angello J. SPARC, a secreted protein associated with cellular proliferation, inhibits cell spreading in vitro and exhibits Ca2+-dependent binding to the extracellular matrix. J Cell Biol 1989;109:341–56.

106

7. COLLAGEN SIGNALING IN CANCER

[91] Sasaki T, Hohenester E, Gohring W, Timpl R. Crystal structure and mapping by site-directed mutagenesis of the collagen-binding epitope of an activated form of BM-40/SPARC/osteonectin. EMBO J 1998;17:1625–34. [92] Brekken RA, Puolakkainen P, Graves DC, Workman G, Lubkin SR, Sage EH. Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J Clin Invest 2003;111:487–95. [93] Puolakkainen PA, Brekken RA, Muneer S, Sage EH. Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol Cancer Res 2004;2:215–24. [94] Arnold SA, Rivera LB, Miller AF, Carbon JG, Dineen SP, Xie Y, Castrillon DH, Sage EH, Puolakkainen P, Bradshaw AD, et al. Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Model Mech 2010;3:57–72. [95] Clark CJ, Sage EH. A prototypic matricellular protein in the tumor microenvironment—where there’s SPARC, there’s fire. J Cell Biochem 2008;104:721–32. [96] Tichet M, Prod’Homme V, Fenouille N, Ambrosetti D, Mallavialle A, Cerezo M, Ohanna M, Audebert S, Rocchi S, Giacchero D, et al. Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. Nat Commun 2015;6:6993. [97] Sato N, Fukushima N, Maehara N, Matsubayashi H, Koopmann J, Su GH, Hruban RH, Goggins M. SPARC/ osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions. Oncogene 2003;22:5021–30. [98] Socha MJ, Said N, Dai Y, Kwong J, Ramalingam P, Trieu V, Desai N, Mok SC, Motamed K. Aberrant promoter methylation of SPARC in ovarian cancer. Neoplasia 2009;11:126–35. [99] Cheetham S, Tang MJ, Mesak F, Kennecke H, Owen D, Tai IT. SPARC promoter hypermethylation in colorectal cancers can be reversed by 5-Aza-20 deoxycytidine to increase SPARC expression and improve therapy response. Br J Cancer 2008;98:1810–9. [100] Heller G, Schmidt WM, Ziegler B, Holzer S, Mullauer L, Bilban M, Zielinski CC, Drach J, Zochbauer-Muller S. Genome-wide transcriptional response to 5-aza-20 -deoxycytidine and trichostatin a in multiple myeloma cells. Cancer Res 2008;68:44–54. [101] Niskakoski A, Kaur S, Staff S, Renkonen-Sinisalo L, Lassus H, Jarvinen HJ, Mecklin JP, Butzow R, Peltomaki P. Epigenetic analysis of sporadic and Lynch-associated ovarian cancers reveals histology-specific patterns of DNA methylation. Epigenetics 2014;9:1577–87. [102] Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011;29:4548–54. [103] Aguilera KY, Rivera LB, Hur H, Carbon JG, Toombs JE, Goldstein CD, Dellinger MT, Castrillon DH, Brekken RA. Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma. Cancer Res 2014;74:1032–44. [104] Carafoli F, Hohenester E. Collagen recognition and transmembrane signalling by discoidin domain receptors. Biochim Biophys Acta 2013;1834:2187–94. [105] Couvelard A, Hu J, Steers G, O’Toole D, Sauvanet A, Belghiti J, Bedossa P, Gatter K, Ruszniewski P, Pezzella F. Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors. Gastroenterology 2006;131:1597–610. [106] Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, Sotiropoulos GC, Radtke A, Lu M, Paul A, Gerken G, et al. Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Mol Cancer 2010;9:227. [107] Miao L, Zhu S, Wang Y, Li Y, Ding J, Dai J, Cai H, Zhang D, Song Y. Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung cancer and promotes cell invasion via epithelial-to-mesenchymal transition. Med Oncol 2013;30:626. [108] Valencia K, Ormazabal C, Zandueta C, Luis-Ravelo D, Anton I, Pajares MJ, Agorreta J, Montuenga LM, Martinez-Canarias S, Leitinger B, et al. Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces cell survival, homing, and colonization in lung cancer bone metastasis. Clin Cancer Res 2012;18:969–80. [109] Ford CE, Lau SK, Zhu CQ, Andersson T, Tsao MS, Vogel WF. Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma. Br J Cancer 2007;96:808–14. [110] Yang SH, Baek HA, Lee HJ, Park HS, Jang KY, Kang MJ, Lee DG, Lee YC, Moon WS, Chung MJ. Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung carcinomas. Oncol Rep 2010;24:311–9.

REFERENCES

107

[111] Weiner HL, Rothman M, Miller DC, Ziff EB. Pediatric brain tumors express multiple receptor tyrosine kinases including novel cell adhesion kinases. Pediatr Neurosurg 1996;25:64–71 [discussion 71-62]. [112] Weiner HL, Huang H, Zagzag D, Boyce H, Lichtenbaum R, Ziff EB. Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors. Neurosurgery 2000;47:1400–9. [113] Yamanaka R, Arao T, Yajima N, Tsuchiya N, Homma J, Tanaka R, Sano M, Oide A, Sekijima M, Nishio K. Identification of expressed genes characterizing long-term survival in malignant glioma patients. Oncogene 2006;25:5994–6002. [114] Cader FZ, Vockerodt M, Bose S, Nagy E, Brundler MA, Kearns P, Murray PG. The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 2013;122: 4237–45. [115] Ongusaha PP, Kim JI, Fang L, Wong TW, Yancopoulos GD, Aaronson SA, Lee SW. p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. EMBO J 2003;22:1289–301. [116] Jian ZX, Sun J, Chen W, Jin HS, Zheng JH, Wu YL. Involvement of discoidin domain 1 receptor in recurrence of hepatocellular carcinoma by genome-wide analysis. Med Oncol 2012;29:3077–82. [117] Das S, Ongusaha PP, Yang YS, Park JM, Aaronson SA, Lee SW. Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappaB pathway activation. Cancer Res 2006;66:8123–30. [118] Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, Keely PJ, Longmore GD. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol 2013;15:677–87. [119] Zhang K, Rodriguez-Aznar E, Yabuta N, Owen RJ, Mingot JM, Nojima H, Nieto MA, Longmore GD. Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation. EMBO J 2012;31:29–43. [120] Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A 2010;107:15449–54. [121] Rodrigues R, Roque L, Espadinha C, Pinto A, Domingues R, Dinis J, Catarino A, Pereira T, Leite V. Comparative genomic hybridization, BRAF, RAS, RET, and oligo-array analysis in aneuploid papillary thyroid carcinomas. Oncol Rep 2007;18:917–26. [122] Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, Teague J, Butler A, Edkins S, Stevens C, et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res 2005;65:7591–5. [123] Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol 2012;13:e418–26. [124] Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, Brace LE, Woods BA, Lin W, Zhang J, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 2011;1:78–89. [125] Zhang S, Bu X, Zhao H, Yu J, Wang Y, Li D, Zhu C, Zhu T, Ren T, Liu X, et al. A host deficiency of discoidin domain receptor 2 (DDR2) inhibits both tumour angiogenesis and metastasis. J Pathol 2014;232:436–48. [126] Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004;4:361–70. [127] Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009;9:28–39. [128] Fang Z, Grutter C, Rauh D. Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem Biol 2013;8:58–70. [129] Schneider R, Becker C, Simard JR, Getlik M, Bohlke N, Janning P, Rauh D. Direct binding assay for the detection of type IV allosteric inhibitors of Abl. J Am Chem Soc 2012;134:9138–41. [130] Day E, Waters B, Spiegel K, Alnadaf T, Manley PW, Buchdunger E, Walker C, Jarai G. Inhibition of collageninduced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharmacol 2008;599:44–53. [131] Rix U, Hantschel O, Durnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, Kaupe I, Bennett KL, Valent P, Colinge J, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 2007;110:4055–63.

108

7. COLLAGEN SIGNALING IN CANCER

[132] Kothiwale S, Borza CM, Lowe Jr. EW, Pozzi A, Meiler J. Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery. Drug Discov Today 2015;20:255–61. [133] Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, Mathieson T, Perrin J, Raida M, Rau C, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol 2007;25:1035–44. [134] Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455:1069–75. [135] Pitini V, Arrigo C, Di Mirto C, Mondello P, Altavilla G. Response to dasatinib in a patient with SQCC of the lung harboring a discoid-receptor-2 and synchronous chronic myelogenous leukemia. Lung Cancer 2013;82:171–2. [136] Gao M, Duan L, Luo J, Zhang L, Lu X, Zhang Y, Zhang Z, Tu Z, Xu Y, Ren X, et al. Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem 2013;56:3281–95. [137] Li Y, Lu X, Ren X, Ding K. Small molecule discoidin domain receptor kinase inhibitors and potential medical applications. J Med Chem 2015;58:3287–301. [138] Richters A, Nguyen HD, Phan T, Simard JR, Grutter C, Engel J, Rauh D. Identification of type II and III DDR2 inhibitors. J Med Chem 2014;57:4252–62.