Selwan, E. M., Finicle, B. T., Kim, S. M. & Edinger, A. L. Attacking the supply wagons to starve cancer cells to death. FEBS Lett. 590, 885–907 (2016).
Forster, J. C., Harriss-Phillips, W. M., Douglass, M. J. & Bezak, E. A review of the development of tumor vasculature and its effects on the tumor microenvironment. Hypoxia 5, 21–32 (2017).
Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).
Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016).
Reid, M. A. et al. The B55α subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol. Cell 50, 200–211 (2013).
Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).
Urasaki, Y., Heath, L. & Xu, C. W. Coupling of glucose deprivation with impaired histone H2B monoubiquitination in tumors. PLOS ONE 7, e36775 (2012).
Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).
Strohecker, A. M. et al. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov. 3, 1272–1285 (2013).
Guo, J. Y. et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev. 27, 1447–1461 (2013).
Lum, J. J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237–248 (2005).
Santana-Codina, N., Mancias, J. D. & Kimmelman, A. C. The role of autophagy in cancer. Annu. Rev. Cancer Biol. 1, 19–39 (2017).
White, E. The role for autophagy in cancer. J. Clin. Invest. 125, 42–46 (2015).
Kimmelman, A. C. & White, E. Autophagy and tumor metabolism. Cell Metab. 25, 1037–1043 (2017).
Chude, C. I. & Amaravadi, R. K. Targeting autophagy in cancer: update on clinical trials and novel inhibitors. Int. J. Mol. Sci. 18, E1279 (2017).
Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528–542 (2017).
Towers, C. G. & Thorburn, A. Therapeutic targeting of autophagy. EBioMedicine 14, 15–23 (2016).
Whatcott, C. J. et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin. Cancer Res. 21, 3561–3568 (2015).
Howe, C. C. & Dietzschold, B. Structural analysis of three subunits of laminin from teratocarcinoma-derived parietal endoderm cells. Dev. Biol. 98, 385–391 (1983).
Howe, C. C. Functional role of laminin carbohydrate. Mol. Cell. Biol. 4, 1–7 (1984).
Cooper, A. R., Kurkinen, M., Taylor, A. & Hogan, B. L. Studies on the biosynthesis of laminin by murine parietal endoderm cells. Eur. J. Biochem. 119, 189–197 (1981).
Hsiao, C.-T. et al. Fibronectin in cell adhesion and migration via N-glycosylation. Oncotarget 8, 70653–70668 (2017).
Kasbaoui, L., Harb, J., Bernard, S. & Meflah, K. Differences in glycosylation state of fibronectin from two rat colon carcinoma cell lines in relation to tumoral progressiveness. Cancer Res. 49, 5317–5322 (1989).
Seguin, L., Desgrosellier, J. S., Weis, S. M. & Cheresh, D. A. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 25, 234–240 (2015).
Muranen, T. et al. Starved epithelial cells uptake extracellular matrix for survival. Nat. Commun. 8, 13989 (2017). This study shows that dietary restriction and nutrient deprivation promote laminin scavenging via α6β4 integrin-mediated endocytosis. Endocytosed laminin maintains essential amino acid levels and supports growth and proliferation when serum and growth factors or nutrients are limited.
Edinger, A. L., Cinalli, R. M. & Thompson, C. B. Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter expression. Dev. Cell 5, 571–582 (2003).
Edinger, A. L. & Thompson, C. B. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol. Biol. Cell 13, 2276–2288 (2002).
Edinger, A. L. Controlling cell growth and survival through regulated nutrient transporter expression. Biochem. J. 406, 1–12 (2007).
Bierie, B. et al. Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc. Natl Acad. Sci. USA 114, E2337–E2346 (2017).
Lu, S., Simin, K., Khan, A. & Mercurio, A. M. Analysis of integrin beta4 expression in human breast cancer: association with basal-like tumors and prognostic significance. Clin. Cancer Res. 14, 1050–1058 (2008).
Rainero, E. et al. Ligand-occupied integrin internalization links nutrient signaling to invasive migration. Cell Rep. 10, 398–413 (2015). This study shows that ovarian cancer cells use α5β1 integrin to take up and degrade fibronectin and use it for fuel. It also demonstrates that mTORC1 negatively regulates fibronectin scavenging.
Winchester, B. Lysosomal metabolism of glycoproteins. Glycobiology 15, 1R–15R (2005).
Memmo, L. M. & McKeown-Longo, P. The alphavbeta5 integrin functions as an endocytic receptor for vitronectin. J. Cell Sci. 111, 425–433 (1998).
Wienke, D., MacFadyen, J. R. & Isacke, C. M. Identification and characterization of the endocytic transmembrane glycoprotein Endo180 as a novel collagen receptor. Mol. Biol. Cell 14, 3592–3604 (2003).
Merlot, A. M., Kalinowski, D. S. & Richardson, D. R. Unraveling the mysteries of serum albumin-more than just a serum protein. Front. Physiol. 5, 299 (2014).
Greish, K. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J. Drug Target 15, 457–464 (2007).
Bern, M., Sand, K. M. K., Nilsen, J., Sandlie, I. & Andersen, J. T. The role of albumin receptors in regulation of albumin homeostasis: implications for drug delivery. J. Control. Release 211, 144–162 (2015).
Davidson, S. M. et al. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat. Med. 23, 235–241 (2017). This study demonstrates that macropinocytosis provides amino acids to orthotopic and autochthonous PDAC tumours in vivo. Fibronectin was also taken up by PDAC tumour cells in vivo.
Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013). This study shows that PDAC tumours with activating mutations in Kras use macropinocytosis to support proliferation under nutrient limitation. Inhibiting macropinocytosis with EIPA selectively inhibits the growth of macropinocytic PDAC xenografts in vivo.
Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715–725 (2007).
Dalloneau, E. et al. Downregulation of the neonatal Fc receptor expression in non-small cell lung cancer tissue is associated with a poor prognosis. Oncotarget 7, 54415–54429 (2016).
Swiercz, R. et al. Loss of expression of the recycling receptor, FcRn, promotes tumor cell growth by increasing albumin consumption. Oncotarget 8, 3528–3541 (2017). This study establishes FcRn as a tumour suppressor that functions by negatively regulating albumin scavenging in breast and prostate cancer cells.
Kim, S. M. et al. PTEN deficiency and AMPK activation promote nutrient scavenging and anabolism in prostate cancer cells. Cancer Discov. 8, 1–18 (2018). This study demonstrates that PTEN loss drives macropinocytosis in prostate tumours and that AMPK is necessary for macropinocytosis. It also provides evidence for a previously unappreciated tumour–microenvironment interaction that supports tumour anabolism: macropinocytosis of necrotic cell debris.
Christensen, E. I. & Birn, H. Megalin and cubilin: multifunctional endocytic receptors. Nat. Rev. Mol. Cell Biol. 3, 256–266 (2002).
Andersen, R. K. et al. Melanoma tumors frequently acquire LRP2/megalin expression, which modulates melanoma cell proliferation and survival rates. Pigment Cell. Melanoma Res. 28, 267–280 (2015).
Schnitzer, J. E. & Bravo, J. High affinity binding, endocytosis, and degradation of conformationally modified albumins. Potential role of gp30 and gp18 as novel scavenger receptors. J. Biol. Chem. 268, 7562–7570 (1993).
Schnitzer, J. E., Sung, A., Horvat, R. & Bravo, J. Preferential interaction of albumin-binding proteins, gp30 and gp18, with conformationally modified albumins. Presence in many cells and tissues with a possible role in catabolism. J. Biol. Chem. 267, 24544–24553 (1992).
Wang, J., Ueno, H., Masuko, T. & Hashimoto, Y. Binding of serum albumin on tumor cells and characterization of the albumin binding protein. J. Biochem. 115, 898–903 (1994).
Sbarouni, E., Georgiadou, P., Kremastinos, D. T. & Voudris, V. Ischemia modified albumin: is this marker of ischemia ready for prime time use? Hellen. J. Cardiol. 49, 260–266 (2008).
Chan, B., Dodsworth, N., Woodrow, J., Tucker, A. & Harris, R. Site-specific N-terminal auto-degradation of human serum albumin. Eur. J. Biochem. 227, 524–528 (1995).
Roy, D. et al. Role of reactive oxygen species on the formation of the novel diagnostic marker ischaemia modified albumin. Heart 92, 113–114 (2006).
Da Silveira, R. A. et al. Ischemia-modified albumin and inflammatory biomarkers in patients with prostate cancer. Clin. Lab 60, 1703–1708 (2014).
Fidan, E. et al. Increased ischemia-modified albumin levels in patients with gastric cancer. Neoplasma 59, 393–397 (2012).
Kerr, M. C. & Teasdale, R. D. Defining macropinocytosis. Traffic 10, 364–371 (2009).
Fujii, M., Kawai, K., Egami, Y. & Araki, N. Dissecting the roles of Rac1 activation and deactivation in macropinocytosis using microscopic photo-manipulation. Sci. Rep. 3, 2385 (2013).
West, M. A., Prescott, A. R., Eskelinen, E. L., Ridley, A. J. & Watts, C. Rac is required for constitutive macropinocytosis by dendritic cells but does not control its downregulation. Curr. Biol. 10, 839–848 (2000).
Yoshida, S., Hoppe, A. D., Araki, N. & Swanson, J. A. Sequential signaling in plasma-membrane domains during macropinosome formation in macrophages. J. Cell Sci. 122, 3250–3261 (2009).
Cox, D. et al. Requirements for both Rac1 and Cdc42 in membrane ruffling and phagocytosis in leukocytes. J. Exp. Med. 186, 1487–1494 (1997).
Yoshida, S., Pacitto, R., Inoki, K. & Swanson, J. Macropinocytosis, mTORC1 and cellular growth control. Cell. Mol. Life Sci. 75, 1227–1239 (2017).
Yoshida, S. et al. Differential signaling during macropinocytosis in response to M-CSF and PMA in macrophages. Front. Physiol. 6, 8 (2015).
Araki, N., Johnson, M. T. & Swanson, J. A. A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J. Cell Biol. 135, 1249–1260 (1996).
Hewlett, L. J., Prescott, A. R. & Watts, C. The coated pit and macropinocytic pathways serve distinct endosome populations. J. Cell Biol. 124, 689–703 (1994).
Veithen, A., Amyere, M., Van Der Smissen, P., Cupers, P. & Courtoy, P. J. Regulation of macropinocytosis in v-Src-transformed fibroblasts: cyclic AMP selectively promotes regurgitation of macropinosomes. J. Cell Sci. 111, 2329–2335 (1998).
Racoosin, E. L. & Swanson, J. A. Macropinosome maturation and fusion with tubular lysosomes in macrophages. J. Cell Biol. 121, 1011–1020 (1993).
Egami, Y., Taguchi, T., Maekawa, M., Arai, H. & Araki, N. Small GTPases and phosphoinositides in the regulatory mechanisms of macropinosome formation and maturation. Front. Physiol. 5, 374 (2014).
Buckley, C. M. & King, J. S. Drinking problems: mechanisms of macropinosome formation and maturation. FEBS J. 284, 3778–3790 (2017).
Bar-Sagi, D. & Feramisco, J. R. Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 233, 1061–1068 (1986).
Tajiri, H. et al. Targeting Ras-driven cancer cell survival and invasion through selective inhibition of DOCK1. Cell Rep. 19, 969–980 (2017). This study shows that dedicator of cytokinesis protein 1 (DOCK1) is necessary for macropinocytosis and cellular invasion. TBOPP, a selective DOCK1 inhibitor, blocks RAS-driven macropinocytosis, tumour growth and metastasis.
Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016).
Seguin, L. et al. Galectin-3, a druggable vulnerability for KRAS-addicted cancers. Cancer Discov. 7, 1464–1479 (2017).
Nofal, M., Zhang, K., Han, S. & Rabinowitz, J. D. mTOR inhibition restores amino acid balance in cells dependent on catabolism of extracellular protein. Mol. Cell 67, 936–946 (2017).
Palm, W. et al. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259–270 (2015).
Olivares, O. et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat. Commun. 8, 16031 (2017).
Abu-Remaileh, M. et al. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358, 807–813 (2017). This study shows that mTORC1 activity is necessary for the efflux of hydrophobic essential amino acids from the lysosome. This study identified signalling pathways regulating lysosomal nutrient efflux.
Guenther, G. G. et al. Loss of TSC2 confers resistance to ceramide and nutrient deprivation. Oncogene 33, 1776–1787 (2014).
Diebold, L. & Chandel, N. S. Mitochondrial ROS regulation of proliferating cells. Free Radic. Biol. Med. 100, 86–93 (2016).
Sen, B. & Johnson, F. M. Regulation of SRC family kinases in human cancers. J. Signal Transduct 2011, 865819 (2011).
Amyere, M. et al. Constitutive macropinocytosis in oncogene-transformed fibroblasts depends on sequential permanent activation of phosphoinositide 3-kinase and phospholipase C. Mol. Biol. Cell 11, 3453–3467 (2000).
Kasahara, K. et al. Role of Src-family kinases in formation and trafficking of macropinosomes. J. Cell. Physiol. 211, 220–232 (2007).
Swanson, J. A. Phorbol esters stimulate macropinocytosis and solute flow through macrophages. J. Cell Sci. 94, 135–142 (1989).
Griner, E. M. & Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nat. Rev. Cancer 7, 281–294 (2007).
Schmees, C. et al. Macropinocytosis of the PDGF β-receptor promotes fibroblast transformation by H-RasG12V. Mol. Biol. Cell 23, 2571–2582 (2012).
Nakase, I., Kobayashi, N. B., Takatani-Nakase, T. & Yoshida, T. Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. Sci. Rep. 5, 10300 (2015).
Dharmawardhane, S. et al. Regulation of macropinocytosis by p21-activated kinase-1. Mol. Biol. Cell 11, 3341–3352 (2000).
Bryant, D. M. et al. EGF induces macropinocytosis and SNX1-modulated recycling of E-cadherin. J. Cell Sci. 120, 1818–1828 (2007).
Guo, G. et al. Ligand-Independent EGFR Signaling. Cancer Res. 75, 3436–3441 (2015).
Farooqi, A. A. & Siddik, Z. H. Platelet-derived growth factor (PDGF) signalling in cancer: rapidly emerging signalling landscape. Cell Biochem. Funct. 33, 257–265 (2015).
Meier, O. et al. Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. J. Cell Biol. 158, 1119–1131 (2002).
Hollander, M. C., Blumenthal, G. M. & Dennis, P. A. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat. Rev. Cancer 11, 289–301 (2011).
Samuels, Y. & Waldman, T. Oncogenic mutations of PIK3CA in human cancers. Curr. Top. Microbiol. Immunol. 347, 21–41 (2010).
Ichim, G. & Tait, S. W. G. A fate worse than death: apoptosis as an oncogenic process. Nat. Rev. Cancer 16, 539–548 (2016).
Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860–866 (2011).
Théry, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2, 569–579 (2002).
Kamerkar, S. et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498–503 (2017).
Zhao, H. et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 5, e10250 (2016). This study shows that exosomes from cancer-associated fibroblasts are taken up by macropinocytosis-dependent and macropinocytosis-independent mechanisms and drive anabolism in prostate cancer cells. Exosomes can provide nutrients (for example, TCA cycle intermediates, amino acids, lipids, and so on).
Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966–979 (2007).
Florey, O., Kim, S. E., Sandoval, C. P., Haynes, C. M. & Overholtzer, M. Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nat. Cell Biol. 13, 1335–1343 (2011).
Hamann, J. C. et al. Entosis is induced by glucose starvation. Cell Rep. 20, 201–210 (2017). This study shows that glucose starvation and AMPK activation promote entosis. It also suggests that metabolically compromised loser cells are more likely to be killed following entosis.
Krajcovic, M., Krishna, S., Akkari, L., Joyce, J. A. & Overholtzer, M. mTOR regulates phagosome and entotic vacuole fission. Mol. Biol. Cell 24, 3736–3745 (2013).
Sun, Q. et al. Competition between human cells by entosis. Cell Res. 24, 1299–1310 (2014).
Lin, S.-C. & Hardie, D. G. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 27, 299–313 (2017).
Garcia, D. & Shaw, R. J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789–800 (2017).
Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).
Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).
Inoki, K., Zhu, T. & Guan, K.-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018).
Faubert, B. et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17, 113–124 (2013).
Liang, J. & Mills, G. B. AMPK: a contextual oncogene or tumor suppressor? Cancer Res. 73, 2929–2935 (2013).
Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).
Edinger, A. L. & Thompson, C. B. An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival. Oncogene 23, 5654–5663 (2004).
Steinberg, F., Heesom, K. J., Bass, M. D. & Cullen, P. J. SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways. J. Cell Biol. 197, 219–230 (2012).
Böttcher, R. T. et al. Sorting nexin 17 prevents lysosomal degradation of β1 integrins by binding to the β1-integrin tail. Nat. Cell Biol. 14, 584–592 (2012).
Ross, E. et al. AMP-activated protein kinase regulates the cell surface proteome and integrin membrane traffic. PLOS ONE 10, e0128013 (2015).
Schaffer, B. E. et al. Identification of AMPK phosphorylation sites reveals a network of proteins involved in cell invasion and facilitates large-scale substrate prediction. Cell Metab. 22, 907–921 (2015).
Zadra, G., Batista, J. L. & Loda, M. Dissecting the dual role of AMPK in cancer: from experimental to human studies. Mol. Cancer Res. 13, 1059–1072 (2015).
Khan, A. S. & Frigo, D. E. A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer. Nat. Rev. Urol. 14, 164–180 (2017).
Saito, Y., Chapple, R. H., Lin, A., Kitano, A. & Nakada, D. AMPK protects leukemia-initiating cells in myeloid leukemias from metabolic stress in the bone marrow. Cell Stem Cell 17, 585–596 (2015). This study demonstrates that AMPK promotes the survival and proliferation of acute myeloid leukaemia under metabolic stress and that AMPK is necessary for established leukaemias. These findings point towards the contextual role of AMPK as an oncogene and the need to develop specific AMPK inhibitors.
Martina, J. A. et al. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Sci. Signal. 7, ra9 (2014). This study shows that TFE3 promotes lysosomal biogenesis and autophagy by increasing the expression of coordinated lysosomal expression and regulation (CLEAR) network genes. mTORC1 inactivation and nutrient stress promote lysosomal biogenesis and function by driving the nuclear translocation of TFE3.
Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5, ra42 (2012). This study shows that TFEB promotes lysosomal biogenesis and autophagy by increasing the expression of CLEAR network genes. mTORC1 inactivation and nutrient stress promote lysosomal biogenesis and function by driving the nuclear translocation of TFEB.
Perera, R. M. et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015). This study demonstrates that the lysosomal biogenesis programme promoted by the MiT/TFE family of transcription factors is essential for PDAC growth and survival. It also suggests that constitutive nuclear localization of MiT/TFE factors is required in tumours that depend on scavenging pathways for nutrient generation.
Peralta, E. R., Martin, B. C. & Edinger, A. L. Differential effects of TBC1D15 and mammalian Vps39 on Rab7 activation state, lysosomal morphology, and growth factor dependence. J. Biol. Chem. 285, 16814–16821 (2010).
Romero Rosales, K., Peralta, E. R., Guenther, G. G., Wong, S. Y. & Edinger, A. L. Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis. Mol. Biol. Cell 20, 2831–2840 (2009).
Kim, S. M. et al. Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways. J. Clin. Invest. 126, 4088–4102 (2016). This study shows that the orally bioavailable small molecule SH-BC-893 starves cancer cells by inhibiting endosome, autophagosome and macropinosome fusion with lysosomes and simultaneously downregulating cell surface nutrient transporters. SH-BC-893 also selectively kills cancer cells in vitro and in vivo, demonstrating that blocking nutrient access can be both safe and effective.
Matthews, H., Ranson, M. & Kelso, M. J. Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? Int. J. Cancer 129, 2051–2061 (2011).
Karmazyn, M. NHE-1: still a viable therapeutic target. J. Mol. Cell Cardiol. 61, 77–82 (2013).
Harguindey, S. et al. Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs — an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. J. Transl Med. 11, 282 (2013).
Murphy, E. & Allen, D. G. Why did the NHE inhibitor clinical trials fail? J. Mol. Cell Cardiol. 46, 137–141 (2009).
Koivusalo, M. et al. Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling. J. Cell Biol. 188, 547–563 (2010).
Hampsch, R. A. et al. Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer. Oncotarget 8, 21806–21817 (2017).
Almiron Bonnin, D. A. et al. Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia. Oncogene 37, 1107–1118 (2017).
Ley, K., Rivera-Nieves, J., Sandborn, W. J. & Shattil, S. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat. Rev. Drug Discov. 15, 173–183 (2016).
Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010).
Bhaskar, V. et al. A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J. Transl Med. 5, 61 (2007).
Bhaskar, V. et al. Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Invest. New Drugs 26, 7–12 (2008).
Ricart, A. D. et al. Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: a phase I, pharmacokinetic, and biological correlative study. Clin. Cancer Res. 14, 7924–7929 (2008).
Bell-McGuinn, K. M. et al. A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer. Gynecol. Oncol. 121, 273–279 (2011).
Khalili, P. et al. A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol. Cancer Ther. 5, 2271–2280 (2006).
Stoeltzing, O. et al. Inhibition of integrin alpha5beta1 function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int. J. Cancer 104, 496–503 (2003).
Cianfrocca, M. E. et al. Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours. Br. J. Cancer 94, 1621–1626 (2006).
McGranahan, N. & Swanton, C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27, 15–26 (2015).
Hu, J. et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 31, 522–529 (2013).
Boroughs, L. K. & DeBerardinis, R. J. Metabolic pathways promoting cancer cell survival and growth. Nat. Cell Biol. 17, 351–359 (2015).
Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).
Wu, N. et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell 49, 1167–1175 (2013).
Chae, Y. K. et al. Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7, 40767–40780 (2016).
Kasznicki, J., Sliwinska, A. & Drzewoski, J. Metformin in cancer prevention and therapy. Ann. Transl Med. 2, 57 (2014).
Wheaton, W. W. et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 3, e02242 (2014).
Mogavero, A. et al. Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci. Rep. 7, 15992 (2017).
Duan, W. et al. Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression. Cancer Lett. 385, 225–233 (2017).
Ming, M. et al. Dose-dependent AMPK-dependent and independent mechanisms of berberine and metformin inhibition of mTORC1, ERK, DNA synthesis and proliferation in pancreatic cancer cells. PLOS ONE 9, e114573 (2014).
Chen, K. et al. Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer. Mol. Cancer 16, 131 (2017).
Weinberg, S. E. & Chandel, N. S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9–15 (2015).
Griss, T. et al. Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLOS Biol. 13, e1002309 (2015).
Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).
Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).
Jeon, S.-M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).
Chhipa, R. R. AMP kinase promotes glioblastoma bioenergetics and tumour growth. Nat. Cell Biol. 20, 823–835 (2018). This study demonstrates that genetic AMPK inhibition in established glioblastomas limits tumour growth and suggests that AMPK inhibitors will not be overtly toxic as systemic AMPK deletion is well-tolerated in adult mice.
Wang, T. et al. Synthesis of improved lysomotropic autophagy inhibitors. J. Med. Chem. 58, 3025–3035 (2015).
Rebecca, V. W. et al. A unified approach to targeting the lysosome’s degradative and growth signaling roles. Cancer Discov. 7, 1266–1283 (2017).
Sui, X. et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 4, e838 (2013).
Muranen, T. et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21, 227–239 (2012).
Eke, I. et al. β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J. Clin. Invest. 122, 1529–1540 (2012).
Huang, C. et al. β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res. 13, R84 (2011).
Kanda, R. et al. Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res. 73, 6243–6253 (2013).
Yang, A. et al. Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms. Cancer Discov. 8, 276–287 (2018).
Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).
Selwan, E. M. & Edinger, A. L. Branched chain amino acid metabolism and cancer: the importance of keeping things in context. Transl Cancer Res. 6, S578–S584 (2017).
Veltman, D. M., Lemieux, M. G., Knecht, D. A. & Insall, R. H. PIP3-dependent macropinocytosis is incompatible with chemotaxis. J. Cell Biol. 204, 497–505 (2014).
Ng, T. L. et al. The AMPK stress response pathway mediates anoikis resistance through inhibition of mTOR and suppression of protein synthesis. Cell Death Differ. 19, 501–510 (2012).
Cai, Q., Yan, L. & Xu, Y. Anoikis resistance is a critical feature of highly aggressive ovarian cancer cells. Oncogene 34, 3315–3324 (2015).
Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).
Padmanabhan, R. & Taneyhill, L. A. Cadherin-6B undergoes macropinocytosis and clathrin-mediated endocytosis during cranial neural crest cell EMT. J. Cell Sci. 128, 1773–1786 (2015).
Syn, N., Wang, L., Sethi, G., Thiery, J.-P. & Goh, B.-C. Exosome-mediated metastasis: from epithelial-mesenchymal transition to escape from immunosurveillance. Trends Pharmacol. Sci. 37, 606–617 (2016).
García-Pérez, B. E. et al. Macropinocytosis is responsible for the uptake of pathogenic and non-pathogenic mycobacteria by B lymphocytes (Raji cells). BMC Microbiol. 12, 246 (2012).
García-Pérez, B. E., Mondragón-Flores, R. & Luna-Herrera, J. Internalization of Mycobacterium tuberculosis by macropinocytosis in non-phagocytic cells. Microb. Pathog. 35, 49–55 (2003).
Méresse, S. et al. Controlling the maturation of pathogen-containing vacuoles: a matter of life and death. Nat. Cell Biol. 1, E183–E188 (1999).
Taghavi, M., Khosravi, A., Mortaz, E., Nikaein, D. & Athari, S. S. Role of pathogen-associated molecular patterns (PAMPS) in immune responses to fungal infections. Eur. J. Pharmacol. 808, 8–13 (2017).
Schaefer, L. Complexity of danger: the diverse nature of damage-associated molecular patterns. J. Biol. Chem. 289, 35237–35245 (2014).
Zhao, W., Qiu, Y. & Kong, D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm. Sin. B 7, 27–37 (2017).
Massacesi, C. et al. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design. Onco Targets Ther. 9, 203–210 (2016).
Janku, F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients. Cancer Treat. Rev. 59, 93–101 (2017).
Castillo-Pichardo, L. et al. The Rac inhibitor EHop-016 inhibits mammary tumor growth and metastasis in a nude mouse model. Transl Oncol. 7, 546–555 (2014).
Okada, T. et al. Integrin-α10 dependency identifies RAC and RICTOR as therapeutic targets in high-grade myxofibrosarcoma. Cancer Discov. 6, 1148–1165 (2016).
Licciulli, S. et al. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J. Biol. Chem. 288, 29105–29114 (2013).
Yeo, D. et al. FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. BMC Cancer 16, 24 (2016).
Dai, R. Y. et al. Implication of transcriptional repression in compound C-induced apoptosis in cancer cells. Cell Death Dis. 4, e883 (2013).
Kim, H.-S. et al. Inhibition of AMP-activated protein kinase sensitizes cancer cells to cisplatin-induced apoptosis via hyper-induction of p53. J. Biol. Chem. 283, 3731–3742 (2008).
Gayle, S. et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood 129, 1768–1778 (2017).
Ohta, T. et al. Bafilomycin A1 induces apoptosis in the human pancreatic cancer cell line Capan-1. J. Pathol. 185, 324–330 (1998).
Lim, J.-H. et al. Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxia-inducible factor-1alpha. Mol. Pharmacol. 70, 1856–1865 (2006).
Yan, Y. et al. Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways. Sci. Rep. 6, 37052 (2016).
Kitazawa, S. et al. Cancer with low cathepsin D levels is susceptible to vacuolar (H+)-ATPase inhibition. Cancer Sci. 108, 1185–1193 (2017).
Chen, B. et al. Azacyclic FTY720 analogues that limit nutrient transporter expression but lack S1P receptor activity and negative chronotropic effects offer a novel and effective strategy to kill cancer cells in vivo. ACS Chem. Biol. 11, 409–414 (2016).
Saito, S. et al. Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling. PLOS ONE 7, e45845 (2012).
Emerling, B. M., Viollet, B., Tormos, K. V. & Chandel, N. S. Compound C inhibits hypoxic activation of HIF-1 independent of AMPK. FEBS Lett. 581, 5727–5731 (2007).