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83: Mechanisms of metastasis by colorectal cancer stem cells
European Journal of Cancer (2014) 50(S5), S21–S22
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Tuesday 8 July 2014 Tuesday 8 July 2014
08:45−09:30
The EMBO Lecture: Hallmarks of Cancer: Applications to Cancer Medicine? 82 Hallmarks of cancer: applications to cancer medicine? ´ erale ´ D. Hanahan1 . 1 Ecole Polytechnique Fed de Lausanne (EPFL), ISREC School of Life Sciences, Lausanne, Switzerland The hallmarks of cancer provide a framework from which to consider the complexity (and underlying commonality) of human cancers. The proposition is that most forms of human cancer acquire, by different ways and means, a similar set of complementary hallmark capabilities that collectively cause the disease. While current and future refinements of the hallmarks conceptualization are arguably useful as a heuristic tool for research designed to elucidate mechanistic underpinnings of the diverse manifestations of the human disease, one can also ask whether there will be beneficial applications to cancer medicine? Is there rationale for therapeutic co-targeting hallmarks of cancer, reasoning that resistance might be harder to acquire if several hallmarks are concurrently impaired? This hypothesis is being tested, both in preclinical models and in clinical trials. Moreover, there are clues that resistance to therapies targeting single hallmarks can be afforded by ‘hallmark switching’, whereby dependence on one hallmark is partially shifted to another so as to evade the functional inhibition, further motivating multi-targeting strategies aimed to circumvent such adaptive resistance. Examples of these emerging applications to cancer medicine will be discussed. Reference(s) Hanahan, D. & Weinberg, R. (2000). The hallmarks of cancer. Cell 100: 57−70. Hanahan, D., & Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144: 346–674. Hanahan, D., & Coussens, L.M. (2012). Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 21: 309–322. Conflict of interest: Advisory board: SAB − Oncology Pfizer, Inc.
Tuesday 8 July 2014
09:30−10:15
The Pezcoller Foundation − EACR Cancer Researcher Award Lecture 83 Mechanisms of metastasis by colorectal cancer stem cells E. Batlle1 . 1 Institute for Research in Biomedicine IRB Barcelona, Oncology Program & ICREA, Barcelona, Spain The inner layer of the intestinal tube, the intestinal epithelium, is in a constant process of renewal. Hundreds of millions of terminally differentiated intestinal cells are replaced by new cells every day during the life of an adult organism. This tremendous regenerative power is ultimately sustained by a small population of intestinal stem cells (ISCs). We have recently discovered that most human colorectal cancers (CRCs) are constituted by cell populations with phenotypes similar to either ISCs or intestinal differentiated cells organized into well-defined compartments. ISC-like cells purified from primary CRC samples generate tumors in immunodeficient mice with high efficiency and display both self-renewal and differentiation capacity whereas differentiated CRC cells are not capable of propagating the disease. Our observations imply that CRC shares a common hierarchy with the intestinal mucosa and that the acquisition of an ISC-like gene program is a central process in the development of metastatic and recurrent CRC. Here I will present our latest data on the mechanisms employed by CRC stem cells to regenerate a new tumor at the metastatic site. We have demonstrated that metastasis relies on a tumor cell
non-autonomous program driven by TGF-beta in the microenvironment. This stromal program confers a survival advantage to the disseminated CRC stem cells during the initial phase of metastasis. We have now investigated the dichotomy of TGF-beta signaling in epithelial versus stromal cells during CRC progression and interrogated mouse models about the efficacy of anti-TGFbeta therapies for CRC treatment. No conflict of interest.
Tuesday 8 July 2014
10:45−12:15
Plenary Symposium: Stem Cells 84 Mesenchymal and MDS stem cells shape an interactive disease unit in the bone marrow A. Trumpp1 , H. Medyouf2 , W.K. Hofmann3 , D. Nowak3 . 1 DKFZ − German Cancer Research Center, and HI-STEM GmbH, Heidelberg, Germany, 2 DKFZ − German Cancer Research Center, Heidelberg, Germany, 3 University Hospital, Mannheim, Germany Myelodysplastic syndromes (MDS) are hematologic disorders characterized by ineffective hematopoiesis, dysplastic bone marrow and increased risk of progression to acute leukemias. Here we show that co-transplantation of lin− CD34+ CD38− cells in-conjunction with mesenchymal-stromal cells both derived from lower risk MDS patients re-establishes long-term disease engraftment in NSG mice. Molecular tracking of xenografted MDS cells allows interrogation of variegated MDS clones. Disease pathogenesis is reliant on specific interactions between MDS hematopoietic cells and MDS MSCs as the latter display greater capability for disease initiation compared to MSCs of healthy subjects. MDS MSCs display deregulated expression of niche regulators including VEGFA, IGFBP2, LIF and N-Cadherin. The “re-programing” of MDS MSCs can be mediated by exposure to MDS hematopoietic cells indicative of microenvironment shaping. This suggests the presence of a MDS stem cell-niche unit in lower risk MDS patients, which if re-transplanted allows the establishment of a xenograft platform opening novel avenues for both MDS analysis and treatment. No conflict of interest. 85 Stem cells in homeostasis and cancer E. Fuchs1 . 1 The Rockefeller University, Howard Hughes Medical Institute, New York, USA Stem cells (SCs) have the ability to self-renew long term and differentiate into one or more tissues. Typically, SCs are used sparingly to replenish cells during normal homeostasis. However, even SCs that are quiescent must be able to respond quickly to injury in order to fuel rapid tissue regeneration. How SCs balance self-renewal and differentiation is of fundamental importance to our understanding of normal tissue maintenance and wound repair. Increasing evidence suggests that the regulatory circuitry governing this balancing act is at the root of some types of tumors both in mice and in humans. The skin is an excellent model system to understand how SCs function in normal tissue generation and how this process goes awry in cancer. We’ve identified SC niches with in the epidermis, hair follicle, sebaceous glands and sweat glands. We’ve learned that different niches become activated in response to different types of injury, and that during normal homeostasis, SC behavior is controlled not only through cues received from their microenvironment but also through signals emanating from their differentiating lineages. We’ve been dissecting how extrinsic signaling to SCs trigger a cascade of transcriptional changes that govern SC activation during tissue development, homeostasis and hair regeneration. Our findings provide new insights into our understanding of the process of SC activation, and in so doing have revealed mechanisms which are also deregulated in a variety of different human cancers. Our goal is to understand how SCs start and stop making tissue, and how this changes in cancer. Our recent discoveries on
0959-8049/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Tuesday 8 July 2014 Tuesday 8 July 2014
08:45−09:30
The EMBO Lecture: Hallmarks of Cancer: Applications to Cancer Medicine? 82 Hallmarks of cancer: applications to cancer medicine? ´ erale ´ D. Hanahan1 . 1 Ecole Polytechnique Fed de Lausanne (EPFL), ISREC School of Life Sciences, Lausanne, Switzerland The hallmarks of cancer provide a framework from which to consider the complexity (and underlying commonality) of human cancers. The proposition is that most forms of human cancer acquire, by different ways and means, a similar set of complementary hallmark capabilities that collectively cause the disease. While current and future refinements of the hallmarks conceptualization are arguably useful as a heuristic tool for research designed to elucidate mechanistic underpinnings of the diverse manifestations of the human disease, one can also ask whether there will be beneficial applications to cancer medicine? Is there rationale for therapeutic co-targeting hallmarks of cancer, reasoning that resistance might be harder to acquire if several hallmarks are concurrently impaired? This hypothesis is being tested, both in preclinical models and in clinical trials. Moreover, there are clues that resistance to therapies targeting single hallmarks can be afforded by ‘hallmark switching’, whereby dependence on one hallmark is partially shifted to another so as to evade the functional inhibition, further motivating multi-targeting strategies aimed to circumvent such adaptive resistance. Examples of these emerging applications to cancer medicine will be discussed. Reference(s) Hanahan, D. & Weinberg, R. (2000). The hallmarks of cancer. Cell 100: 57−70. Hanahan, D., & Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144: 346–674. Hanahan, D., & Coussens, L.M. (2012). Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 21: 309–322. Conflict of interest: Advisory board: SAB − Oncology Pfizer, Inc.
Tuesday 8 July 2014
09:30−10:15
The Pezcoller Foundation − EACR Cancer Researcher Award Lecture 83 Mechanisms of metastasis by colorectal cancer stem cells E. Batlle1 . 1 Institute for Research in Biomedicine IRB Barcelona, Oncology Program & ICREA, Barcelona, Spain The inner layer of the intestinal tube, the intestinal epithelium, is in a constant process of renewal. Hundreds of millions of terminally differentiated intestinal cells are replaced by new cells every day during the life of an adult organism. This tremendous regenerative power is ultimately sustained by a small population of intestinal stem cells (ISCs). We have recently discovered that most human colorectal cancers (CRCs) are constituted by cell populations with phenotypes similar to either ISCs or intestinal differentiated cells organized into well-defined compartments. ISC-like cells purified from primary CRC samples generate tumors in immunodeficient mice with high efficiency and display both self-renewal and differentiation capacity whereas differentiated CRC cells are not capable of propagating the disease. Our observations imply that CRC shares a common hierarchy with the intestinal mucosa and that the acquisition of an ISC-like gene program is a central process in the development of metastatic and recurrent CRC. Here I will present our latest data on the mechanisms employed by CRC stem cells to regenerate a new tumor at the metastatic site. We have demonstrated that metastasis relies on a tumor cell
non-autonomous program driven by TGF-beta in the microenvironment. This stromal program confers a survival advantage to the disseminated CRC stem cells during the initial phase of metastasis. We have now investigated the dichotomy of TGF-beta signaling in epithelial versus stromal cells during CRC progression and interrogated mouse models about the efficacy of anti-TGFbeta therapies for CRC treatment. No conflict of interest.
Tuesday 8 July 2014
10:45−12:15
Plenary Symposium: Stem Cells 84 Mesenchymal and MDS stem cells shape an interactive disease unit in the bone marrow A. Trumpp1 , H. Medyouf2 , W.K. Hofmann3 , D. Nowak3 . 1 DKFZ − German Cancer Research Center, and HI-STEM GmbH, Heidelberg, Germany, 2 DKFZ − German Cancer Research Center, Heidelberg, Germany, 3 University Hospital, Mannheim, Germany Myelodysplastic syndromes (MDS) are hematologic disorders characterized by ineffective hematopoiesis, dysplastic bone marrow and increased risk of progression to acute leukemias. Here we show that co-transplantation of lin− CD34+ CD38− cells in-conjunction with mesenchymal-stromal cells both derived from lower risk MDS patients re-establishes long-term disease engraftment in NSG mice. Molecular tracking of xenografted MDS cells allows interrogation of variegated MDS clones. Disease pathogenesis is reliant on specific interactions between MDS hematopoietic cells and MDS MSCs as the latter display greater capability for disease initiation compared to MSCs of healthy subjects. MDS MSCs display deregulated expression of niche regulators including VEGFA, IGFBP2, LIF and N-Cadherin. The “re-programing” of MDS MSCs can be mediated by exposure to MDS hematopoietic cells indicative of microenvironment shaping. This suggests the presence of a MDS stem cell-niche unit in lower risk MDS patients, which if re-transplanted allows the establishment of a xenograft platform opening novel avenues for both MDS analysis and treatment. No conflict of interest. 85 Stem cells in homeostasis and cancer E. Fuchs1 . 1 The Rockefeller University, Howard Hughes Medical Institute, New York, USA Stem cells (SCs) have the ability to self-renew long term and differentiate into one or more tissues. Typically, SCs are used sparingly to replenish cells during normal homeostasis. However, even SCs that are quiescent must be able to respond quickly to injury in order to fuel rapid tissue regeneration. How SCs balance self-renewal and differentiation is of fundamental importance to our understanding of normal tissue maintenance and wound repair. Increasing evidence suggests that the regulatory circuitry governing this balancing act is at the root of some types of tumors both in mice and in humans. The skin is an excellent model system to understand how SCs function in normal tissue generation and how this process goes awry in cancer. We’ve identified SC niches with in the epidermis, hair follicle, sebaceous glands and sweat glands. We’ve learned that different niches become activated in response to different types of injury, and that during normal homeostasis, SC behavior is controlled not only through cues received from their microenvironment but also through signals emanating from their differentiating lineages. We’ve been dissecting how extrinsic signaling to SCs trigger a cascade of transcriptional changes that govern SC activation during tissue development, homeostasis and hair regeneration. Our findings provide new insights into our understanding of the process of SC activation, and in so doing have revealed mechanisms which are also deregulated in a variety of different human cancers. Our goal is to understand how SCs start and stop making tissue, and how this changes in cancer. Our recent discoveries on
0959-8049/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.