Host Control of Tumor Feeding: Autophagy Holds the Key

Cell Metabolism

Previews precursors being pre-disposed to efferocytotic proficiency (Hamers et al., 2019). Phagocyte lineage may also be pertinent; a subset of foam cells present in atherosclerotic lesions that express ‘‘macrophage’’ lineage markers are in fact derived from vascular smooth muscle cells and are poorly phagocytic (DiRenzo et al., 2017; Vengrenyuk et al., 2015). The interplay between metabolic signaling and inflammation in distinct efferocyte populations presents an exciting new avenue of undiscovered biology with clinical potential in the treatment of inflammatory diseases.

ACKNOWLEDGMENTS This work was supported by the Canadian Institutes for Health Research (PJT-391187 and Can-

ada Research Chair to M.O.) and the Heart and Stroke Foundation of Canada (M.O.).

program to promote glucose uptake and lactate release. Nature 563, 714–718.

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Van den Bossche, J., O’Neill, L.A., and Menon, D. (2017). Macrophage immunometabolism: where are we (going)? Trends Immunol. 38, 395–406.

DiRenzo, D., Owens, G.K., and Leeper, N.J. (2017). ‘‘Attack of the clones’’: commonalities between cancer and atherosclerosis. Circ. Res. 120, 624–626. Hamers, A.A.J., Dinh, H.Q., Thomas, G.D., Marcovecchio, P., Blatchley, A., Nakao, C.S., Kim, C., McSkimming, C., Taylor, A.M., Nguyen, A.T., et al. (2019). Human monocyte heterogeneity as revealed by high-dimensional mass cytometry. Arterioscler. Thromb. Vasc. Biol. 39, 25–36. Heckmann, B.L., Boada-Romero, E., Cunha, L.D., Magne, J., and Green, D.R. (2017). LC3-associated phagocytosis and inflammation. J. Mol. Biol. 429, 3561–3576. Morioka, S., Perry, J.S.A., Raymond, M.H., Medina, C.B., Zhu, Y., Zhao, L., Serbulea, V., Onengut-Gumuscu, S., Leitinger, N., Kucenas, S., et al. (2018). Efferocytosis induces a novel SLC

Vengrenyuk, Y., Nishi, H., Long, X., Ouimet, M., Savji, N., Martinez, F.O., Cassella, C.P., Moore, K.J., Ramsey, S.A., Miano, J.M., and Fisher, E.A. (2015). Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler. Thromb. Vasc. Biol. 35, 535–546. Yurdagul, A., Jr., Doran, A.C., Cai, B., Fredman, G., and Tabas, I.A. (2018). Mechanisms and consequences of defective efferocytosis in atherosclerosis. Front. Cardiovasc. Med. 4, 86. Zhang, S., Weinberg, S., DeBerge, M., Gainullina, A., Schipma, M., Kinchen, J.M., Ben-Sahra, I., Gius, D.R., Charvet, L.Y., Chandel, N.S., et al. (2018). Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab. 29, this issue, 443–456.

Host Control of Tumor Feeding: Autophagy Holds the Key Anthony Venida1 and Rushika M. Perera1,2,3,* 1Department

of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA 3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2019.01.009 2Department

Cancer cells are dependent on functional autophagy both within their cytoplasm and systemically in the host to maintain growth. How systemic autophagy directly contributes to tumor growth remains unclear. In a study published in Nature, Poillet-Perez et al. (2018) show that host autophagy helps to maintain the levels of circulating arginine that feed tumor growth. A key feature of many cancers is their ability to activate nutrient scavenging pathways that help to fuel the metabolic requirements of rapid, uncontrolled growth. Autophagy is a highly conserved intracellular clearance and recycling pathway that maintains metabolic homeostasis and survival of cells during periods of starvation and stress (Kaur and Debnath, 2015). Accordingly, cancers as diverse as lung, breast, pancreas, melanoma, and colorectal carcinomas co-opt autophagy to maintain their metabolic, proliferative, and survival capacity, and they are highly vulnerable

to autophagy suppression (Onorati et al., 2018). In addition to the wellestablished cell-intrinsic role for autophagy in tumorigenesis, recent studies have suggested that elevated autophagy in the host can also aid tumor growth (Sousa et al., 2016; Katheder et al., 2017). Strong evidence for this idea derives from acute, systemic suppression of the essential autophagy gene Atg7, which leads to dramatic regression of aggressive KRAS-driven lung cancer in mice (Karsli-Uzunbas et al., 2014). How the combined action of tumor-cell-autonomous and host

236 Cell Metabolism 29, February 5, 2019 ª 2019 Elsevier Inc.

autophagy synergizes to fuel neoplastic growth—and the specific contributions of host autophagy to tumor cell metabolism—is a wide open question. The study by Poillet-Perez and colleagues sheds light on these questions by revealing a critical and mechanistically surprising role for autophagy in the host liver for sustaining the growth of transplanted cancer cells (Figure 1). In their study, the authors selected a diverse panel of mouse cancer cell lines derived from melanoma, urothelial carcinoma, and non-small-cell lung cancer (NSCLC) models and measured their

Cell Metabolism

Previews growth rate as allografts and for tumor growth. Taken in syngeneic autophagytogether, these data indicate competent (Atg7+/+) or -defithat host autophagy supports cient (Atg7D/D) host mice. tumorigenesis by maintaining Strikingly, several allografted levels of circulating arginine. cancer cell lines showed Several intriguing questions impaired growth in Atg7D/D arise from this study. First, hosts compared to growth in what are the underlying adapAtg7+/+ hosts, whereas a subtive mechanisms that explain set of the cell lines were resiswhy some cancer cell lines tant to systemic autophagy are resistant to host autodeletion and grew equally phagy deficiency while others well in Atg7+/+ and Atg7D/D are sensitive to its loss? It hosts. To uncover the underis interesting to note that, lying mechanism for depenin this study, the resistant dence on host autophagy and sensitive melanoma Figure 1. Host Autophagy Maintains Circulating Arginine That in the sensitive lines, the aucell lines share similar geFeeds Tumor Growth Growth of tumor allografts in autophagy-competent host mice is mediated in thors performed comparative netics (BrafV600E, PTEN, and part through uptake of circulating arginine (red circle). Systemic or liverCDKN2A homozygous loss) metabolite profiling of serum specific loss of autophagy induces hepatocyte-mediated release of ARG1 (Poillet-Perez et al., 2018) from Atg7+/+ and Atg7D/D and subsequent depletion of circulating arginine, leading to reduced growth mice. The host blood supply and dependence on exogeof transplanted tumors. is a major source of nutrients nous arginine in vitro. One for the tumor, and several possibility is that alternate circulating metabolites were significantly lating ARG1 suggests that host auto- scavenging pathways may be activated altered in Atg7D/D hosts, most prominently phagy deletion leads to release of ARG1 in resistant tumors that help to maintain a significant drop in arginine concentra- by the liver into the circulation. The au- intra-tumoral arginine levels despite, or tion. Explaining their dependence on thors hypothesize that increased release in response to, decreased circulating circulating arginine as a nutrient source, of ARG1 from the liver is directly respon- arginine. For example, induction of macseveral of the cancer cell lines tested sible for the observed drop in arginine ropinocytosis, the process of bulk uptake lacked expression of key arginine biosyn- levels in the context of systemic Atg7 of extracellular protein that is subsethesis enzymes, including arginino- loss. Consistent with this hypothesis, the quently degraded via the lysosome, may succinate lyase (ASS1) and ornithine authors found increased levels of orni- provide a source of arginine in these cells transcarbamylase (OTC). Defective argi- thine in the circulation and in the tumor that sustains tumor growth in autophagynine synthesis is a common metabolic allografts growing in Atg7D/D mice. Impor- deficient hosts. vulnerability in cancer known as arginine tantly, dietary arginine supplementation It is notable that liver-specific autoauxotrophy (Patil et al., 2016), and it is miti- was able to partially rescue circulating phagy inactivation is not as potent in supgated by increased uptake of exogenous arginine levels and tumor growth in pressing tumor growth as whole-body arginine. Hence, the reduced growth rate Atg7D/D hosts. suppression. The authors propose that of cancer cells lacking ASS1 and OTC in Several conditions, including liver dam- autophagy activation in neighboring stroAtg7D/D hosts likely reflects a dependence age and inflammation, are known to stim- mal cells and other distant organs could on systemic autophagy for supplying argi- ulate release of ARG1 from hepatocytes release nutrients that help feed tumor nine to tumor cells. Interestingly, cell lines (Morris, 2012). Consistently, the authors cells, as has been reported previously that were able to grow despite loss of observed that Atg7D/D hosts display fatty (Sousa et al., 2016; Katheder et al., host autophagy also lacked expression of liver disease, a hallmark of liver dysfunc- 2017). Whether, as shown in Drosophila ASS1 and OTC, suggesting that these tion. Based on these observations, the (Katheder et al., 2017), mammalian tulines either harbor intrinsic resistance to authors tested whether liver-specific mors actively trigger host autophagy at autophagy deficiency that is independent deletion of Atg7 would lead to ARG1 distant sites remains largely unknown. of arginine auxotrophy or are able to release, depletion of circulating arginine, Serum proteomics analyses similar to activate compensatory pathways (dis- and subsequent impairment of tumor those performed in the present study cussed below). growth in a similar manner to that may aid in identifying circulating cytoTo determine how circulating arginine is observed following whole-body Atg7 kines and signaling molecules that enable depleted in Atg7D/D host mice, the authors deletion. Indeed, liver-specific deletion remote control of autophagy induction in next performed serum proteomics anal- of Atg7 recapitulated the phenotypes of distant tissues by tumor cells. ysis and identified the arginine-degrading whole-body Atg7D/D hosts, albeit to a Finally, despite important roles for autoenzyme arginase 1 (ARG1) as significantly lesser degree. Whole-body conditional phagy in modulation of immune cell enriched in serum from Atg7D/D hosts deletion and liver-specific deletion of function (Clarke and Simon, 2018), the relative to Atg7+/+ controls. ARG1 is a Atg5 displayed similar results to Atg7 defi- authors’ data do not support a role for liver-specific enzyme that degrades argi- ciency, confirming dependency on auto- the immune system in suppression of nine to ornithine. Thus increased circu- phagy for maintenance of serum arginine tumor growth in autophagy-deficient Cell Metabolism 29, February 5, 2019 237

Cell Metabolism

Previews hosts. Future studies analyzing tumors with greater mutational burdens and heightened immunogenicity may uncover an important role for immune cell subsets in regulation of tumor growth following systemic autophagy suppression. In summary, this work points to an important role for host autophagy in facilitating the growth of a subset of melanoma, NSCLC, and urothelial tumors, and it highlights a key function for the liver in regulating the levels of circulating arginine (Figure 1). These results suggest that therapeutic amino acid depletion induced via either small molecules or recombinant enzymes may be an effective therapeutic strategy. Accordingly, phase I and II clinical trials utilizing pegylated derivatives of recombinant mammalian arginase or microbial arginine deiminase have displayed some clinical benefit and low toxicity in subsets of patients with ASS1negative tumors (Delage et al., 2010). Together, these findings support further investigation into whether nutrient deprivation as a therapeutic strategy would

be effective settings.

across

diverse

tumor

Katheder, N.S., Khezri, R., O’Farrell, F., Schultz, S.W., Jain, A., Rahman, M.M., Schink, K.O., Theodossiou, T.A., Johansen, T., Juha´sz, G., et al. (2017). Microenvironmental autophagy promotes tumour growth. Nature 541, 417–420.

ACKNOWLEDGMENTS A.V. is supported by a National Science Foundation Graduate Research Fellowship. R.M.P. is supported by an NIH Director’s New Innovator Award (1DP2CA216364) and the Damon Runyon-Rachleff Innovation Award.

Kaur, J., and Debnath, J. (2015). Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461–472. Morris, S.M., Jr. (2012). Arginases and arginine deficiency syndromes. Curr. Opin. Clin. Nutr. Metab. Care 15, 64–70.

REFERENCES

Onorati, A.V., Dyczynski, M., Ojha, R., and Amaravadi, R.K. (2018). Targeting autophagy in cancer. Cancer 124, 3307–3318.

Clarke, A.J., and Simon, A.K. (2018). Autophagy in the renewal, differentiation and homeostasis of immune cells. Nat. Rev. Immunol. Published online December 7, 2018 https://doi.org/10.1038/s41577018-0095-2.

Patil, M.D., Bhaumik, J., Babykutty, S., Banerjee, U.C., and Fukumura, D. (2016). Arginine dependence of tumor cells: targeting a chink in cancer’s armor. Oncogene 35, 4957–4972.

Delage, B., Fennell, D.A., Nicholson, L., McNeish, I., Lemoine, N.R., Crook, T., and Szlosarek, P.W. (2010). Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int. J. Cancer 126, 2762–2772.

Poillet-Perez, L., Xie, X., Zhan, L., Yang, Y., Sharp, D.W., Hu, Z.S., Su, X., Maganti, A., Jiang, C., Lu, W., et al. (2018). Autophagy maintains tumour growth through circulating arginine. Nature 563, 569–573.

Karsli-Uzunbas, G., Guo, J.Y., Price, S., Teng, X., Laddha, S.V., Khor, S., Kalaany, N.Y., Jacks, T., Chan, C.S., Rabinowitz, J.D., and White, E. (2014). Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914–927.

Sousa, C.M., Biancur, D.E., Wang, X., Halbrook, C.J., Sherman, M.H., Zhang, L., Kremer, D., Hwang, R.F., Witkiewicz, A.K., Ying, H., et al. (2016). Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483.

AMPK-Mediated Lysosome Biogenesis in Lung Cancer Growth Krushna C. Patra,1,2,3 Vajira K. Weerasekara,1,2,3 and Nabeel Bardeesy1,2,3,* 1Massachusetts

General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA 3Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA 02113, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.12.011 2Center

Cancer cells must adapt to metabolic stress during tumor progression. In this issue of Cell Metabolism, Eichner et al. (2019) report that lung cancer development in genetically engineered mice requires the energy sensor AMP-activated protein kinase (AMPK). Their findings suggest that AMPK-mediated induction of lysosomal function supports cancer cell fitness, particularly during the early stages of tumorigenesis. Neoplastic cells in evolving solid tumors are subject to changing metabolic stresses. Increased nutrient demand and oxidative stress due to cell growth or oncogenic signaling and limitations in nutrient availability can create barriers to tumorigenesis. In turn, adaptive processes must be engaged to restore metabolic homeostasis. A major, evolutionarily

conserved sensor of nutrient states is the AMP-activated protein kinase (AMPK). In response to diverse cellular stresses, AMPK drives metabolic adaptation through balancing anabolic and catabolic pathways. Key outputs include suppression of protein and fatty acid synthesis, induction of fatty acid oxidation, promotion of glucose uptake, and nutrient

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scavenging via macroautophagy and macropinocytosis. Whether AMPK restrains tumorigenesis in vivo (e.g., by preventing aberrant activation of biosynthetic processes) or supports it (e.g., by enabling metabolic adaptation) has not been fully resolved. The LKB1 tumor suppressor (liver kinase B1; encoded by the STK11 gene) is one of two major