Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Nutrient scavenging in cancer

Abstract

While cancer cell proliferation depends on access to extracellular nutrients, inadequate tumour perfusion means that glucose, amino acids and lipids are often in short supply. To overcome this obstacle to growth, cancer cells utilize multiple scavenging strategies, obtaining macromolecules from the microenvironment and breaking them down in the lysosome to produce substrates for ATP generation and anabolism. Recent studies have revealed four scavenging pathways that support cancer cell proliferation in low-nutrient environments: scavenging of extracellular matrix proteins via integrins, receptor-mediated albumin uptake and catabolism, macropinocytic consumption of multiple components of the tumour microenvironment and the engulfment and degradation of entire live cells via entosis. New evidence suggests that blocking these pathways alone or in combination could provide substantial benefits to patients with incurable solid tumours. Both US Food and Drug Administration (FDA)-approved drugs and several agents in preclinical or clinical development shut down individual or multiple scavenging pathways. These therapies may increase the extent and durability of tumour growth inhibition and/or prevent the development of resistance when used in combination with existing treatments. This Review summarizes the evidence suggesting that scavenging pathways drive tumour growth, highlights recent advances that define the oncogenic signal transduction pathways that regulate scavenging and considers the benefits and detriments of therapeutic strategies targeting scavenging that are currently under development.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Receptor-mediated scavenging of albumin and extracellular matrix proteins.
Fig. 2: Scavenging through macropinocytosis and entosis.
Fig. 3: Pathway specificity in nutrient scavenging.

References

  1. 1.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    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).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    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).

    CAS  PubMed  Google Scholar 

  6. 6.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Urasaki, Y., Heath, L. & Xu, C. W. Coupling of glucose deprivation with impaired histone H2B monoubiquitination in tumors. PLOS ONE 7, e36775 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Strohecker, A. M. et al. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov. 3, 1272–1285 (2013).

    CAS  PubMed  Google Scholar 

  10. 10.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Lum, J. J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237–248 (2005).

    CAS  PubMed  Google Scholar 

  12. 12.

    Santana-Codina, N., Mancias, J. D. & Kimmelman, A. C. The role of autophagy in cancer. Annu. Rev. Cancer Biol. 1, 19–39 (2017).

    Google Scholar 

  13. 13.

    White, E. The role for autophagy in cancer. J. Clin. Invest. 125, 42–46 (2015).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Kimmelman, A. C. & White, E. Autophagy and tumor metabolism. Cell Metab. 25, 1037–1043 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Chude, C. I. & Amaravadi, R. K. Targeting autophagy in cancer: update on clinical trials and novel inhibitors. Int. J. Mol. Sci. 18, E1279 (2017).

    PubMed  Google Scholar 

  16. 16.

    Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528–542 (2017).

    CAS  PubMed  Google Scholar 

  17. 17.

    Towers, C. G. & Thorburn, A. Therapeutic targeting of autophagy. EBioMedicine 14, 15–23 (2016).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Whatcott, C. J. et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin. Cancer Res. 21, 3561–3568 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Howe, C. C. & Dietzschold, B. Structural analysis of three subunits of laminin from teratocarcinoma-derived parietal endoderm cells. Dev. Biol. 98, 385–391 (1983).

    CAS  PubMed  Google Scholar 

  20. 20.

    Howe, C. C. Functional role of laminin carbohydrate. Mol. Cell. Biol. 4, 1–7 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    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).

    CAS  PubMed  Google Scholar 

  22. 22.

    Hsiao, C.-T. et al. Fibronectin in cell adhesion and migration via N-glycosylation. Oncotarget 8, 70653–70668 (2017).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    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).

    CAS  PubMed  Google Scholar 

  24. 24.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    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).

    CAS  PubMed  Google Scholar 

  27. 27.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Edinger, A. L. Controlling cell growth and survival through regulated nutrient transporter expression. Biochem. J. 406, 1–12 (2007).

    CAS  PubMed  Google Scholar 

  29. 29.

    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).

    CAS  PubMed  Google Scholar 

  30. 30.

    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).

    CAS  PubMed  Google Scholar 

  31. 31.

    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.

    CAS  Google Scholar 

  32. 32.

    Winchester, B. Lysosomal metabolism of glycoproteins. Glycobiology 15, 1R–15R (2005).

    CAS  PubMed  Google Scholar 

  33. 33.

    Memmo, L. M. & McKeown-Longo, P. The alphavbeta5 integrin functions as an endocytic receptor for vitronectin. J. Cell Sci. 111, 425–433 (1998).

    CAS  PubMed  Google Scholar 

  34. 34.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    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).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    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).

    CAS  PubMed  Google Scholar 

  37. 37.

    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).

    CAS  PubMed  Google Scholar 

  38. 38.

    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.

    CAS  PubMed  Google Scholar 

  39. 39.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715–725 (2007).

    CAS  PubMed  Google Scholar 

  41. 41.

    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).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    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.

    PubMed  Google Scholar 

  43. 43.

    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.

    Google Scholar 

  44. 44.

    Christensen, E. I. & Birn, H. Megalin and cubilin: multifunctional endocytic receptors. Nat. Rev. Mol. Cell Biol. 3, 256–266 (2002).

    CAS  PubMed  Google Scholar 

  45. 45.

    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).

    CAS  PubMed  Google Scholar 

  46. 46.

    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).

    CAS  PubMed  Google Scholar 

  47. 47.

    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).

    CAS  PubMed  Google Scholar 

  48. 48.

    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).

    CAS  PubMed  Google Scholar 

  49. 49.

    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).

    Google Scholar 

  50. 50.

    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).

    CAS  PubMed  Google Scholar 

  51. 51.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Da Silveira, R. A. et al. Ischemia-modified albumin and inflammatory biomarkers in patients with prostate cancer. Clin. Lab 60, 1703–1708 (2014).

    PubMed  Google Scholar 

  53. 53.

    Fidan, E. et al. Increased ischemia-modified albumin levels in patients with gastric cancer. Neoplasma 59, 393–397 (2012).

    CAS  PubMed  Google Scholar 

  54. 54.

    Kerr, M. C. & Teasdale, R. D. Defining macropinocytosis. Traffic 10, 364–371 (2009).

    CAS  PubMed  Google Scholar 

  55. 55.

    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).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    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).

    CAS  PubMed  Google Scholar 

  57. 57.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Cox, D. et al. Requirements for both Rac1 and Cdc42 in membrane ruffling and phagocytosis in leukocytes. J. Exp. Med. 186, 1487–1494 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Yoshida, S., Pacitto, R., Inoki, K. & Swanson, J. Macropinocytosis, mTORC1 and cellular growth control. Cell. Mol. Life Sci. 75, 1227–1239 (2017).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Yoshida, S. et al. Differential signaling during macropinocytosis in response to M-CSF and PMA in macrophages. Front. Physiol. 6, 8 (2015).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    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).

    CAS  PubMed  Google Scholar 

  62. 62.

    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).

    CAS  PubMed  Google Scholar 

  63. 63.

    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).

    CAS  PubMed  Google Scholar 

  64. 64.

    Racoosin, E. L. & Swanson, J. A. Macropinosome maturation and fusion with tubular lysosomes in macrophages. J. Cell Biol. 121, 1011–1020 (1993).

    CAS  PubMed  Google Scholar 

  65. 65.

    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).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Buckley, C. M. & King, J. S. Drinking problems: mechanisms of macropinosome formation and maturation. FEBS J. 284, 3778–3790 (2017).

    CAS  PubMed  Google Scholar 

  67. 67.

    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).

    CAS  PubMed  Google Scholar 

  68. 68.

    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.

    CAS  PubMed  Google Scholar 

  69. 69.

    Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Seguin, L. et al. Galectin-3, a druggable vulnerability for KRAS-addicted cancers. Cancer Discov. 7, 1464–1479 (2017).

    CAS  PubMed  Google Scholar 

  71. 71.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Palm, W. et al. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259–270 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Olivares, O. et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat. Commun. 8, 16031 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    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.

    CAS  PubMed  Google Scholar 

  75. 75.

    Guenther, G. G. et al. Loss of TSC2 confers resistance to ceramide and nutrient deprivation. Oncogene 33, 1776–1787 (2014).

    CAS  PubMed  Google Scholar 

  76. 76.

    Diebold, L. & Chandel, N. S. Mitochondrial ROS regulation of proliferating cells. Free Radic. Biol. Med. 100, 86–93 (2016).

    CAS  PubMed  Google Scholar 

  77. 77.

    Sen, B. & Johnson, F. M. Regulation of SRC family kinases in human cancers. J. Signal Transduct 2011, 865819 (2011).

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Kasahara, K. et al. Role of Src-family kinases in formation and trafficking of macropinosomes. J. Cell. Physiol. 211, 220–232 (2007).

    CAS  PubMed  Google Scholar 

  80. 80.

    Swanson, J. A. Phorbol esters stimulate macropinocytosis and solute flow through macrophages. J. Cell Sci. 94, 135–142 (1989).

    CAS  PubMed  Google Scholar 

  81. 81.

    Griner, E. M. & Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nat. Rev. Cancer 7, 281–294 (2007).

    CAS  PubMed  Google Scholar 

  82. 82.

    Schmees, C. et al. Macropinocytosis of the PDGF β-receptor promotes fibroblast transformation by H-RasG12V. Mol. Biol. Cell 23, 2571–2582 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Dharmawardhane, S. et al. Regulation of macropinocytosis by p21-activated kinase-1. Mol. Biol. Cell 11, 3341–3352 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Bryant, D. M. et al. EGF induces macropinocytosis and SNX1-modulated recycling of E-cadherin. J. Cell Sci. 120, 1818–1828 (2007).

    CAS  PubMed  Google Scholar 

  86. 86.

    Guo, G. et al. Ligand-Independent EGFR Signaling. Cancer Res. 75, 3436–3441 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Meier, O. et al. Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. J. Cell Biol. 158, 1119–1131 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    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).

    CAS  PubMed  Google Scholar 

  90. 90.

    Samuels, Y. & Waldman, T. Oncogenic mutations of PIK3CA in human cancers. Curr. Top. Microbiol. Immunol. 347, 21–41 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Ichim, G. & Tait, S. W. G. A fate worse than death: apoptosis as an oncogenic process. Nat. Rev. Cancer 16, 539–548 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860–866 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Théry, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2, 569–579 (2002).

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Kamerkar, S. et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498–503 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    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).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966–979 (2007).

    CAS  Google Scholar 

  97. 97.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Sun, Q. et al. Competition between human cells by entosis. Cell Res. 24, 1299–1310 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Lin, S.-C. & Hardie, D. G. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 27, 299–313 (2017).

    PubMed  Google Scholar 

  102. 102.

    Garcia, D. & Shaw, R. J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789–800 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Inoki, K., Zhu, T. & Guan, K.-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    CAS  PubMed  Google Scholar 

  106. 106.

    Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018).

    CAS  PubMed  Google Scholar 

  107. 107.

    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).

    CAS  PubMed  Google Scholar 

  108. 108.

    Liang, J. & Mills, G. B. AMPK: a contextual oncogene or tumor suppressor? Cancer Res. 73, 2929–2935 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).

    CAS  Google Scholar 

  110. 110.

    Edinger, A. L. & Thompson, C. B. An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival. Oncogene 23, 5654–5663 (2004).

    CAS  PubMed  Google Scholar 

  111. 111.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    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).

    PubMed  Google Scholar 

  113. 113.

    Ross, E. et al. AMP-activated protein kinase regulates the cell surface proteome and integrin membrane traffic. PLOS ONE 10, e0128013 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    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.

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    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.

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    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).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    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.

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    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).

    CAS  PubMed  Google Scholar 

  125. 125.

    Karmazyn, M. NHE-1: still a viable therapeutic target. J. Mol. Cell Cardiol. 61, 77–82 (2013).

    CAS  PubMed  Google Scholar 

  126. 126.

    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).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Murphy, E. & Allen, D. G. Why did the NHE inhibitor clinical trials fail? J. Mol. Cell Cardiol. 46, 137–141 (2009).

    CAS  PubMed  Google Scholar 

  128. 128.

    Koivusalo, M. et al. Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling. J. Cell Biol. 188, 547–563 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    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).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    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).

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    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).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    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).

    CAS  PubMed  Google Scholar 

  135. 135.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    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).

    CAS  PubMed  Google Scholar 

  138. 138.

    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).

    CAS  PubMed  Google Scholar 

  139. 139.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    McGranahan, N. & Swanton, C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27, 15–26 (2015).

    CAS  PubMed  Google Scholar 

  141. 141.

    Hu, J. et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 31, 522–529 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Boroughs, L. K. & DeBerardinis, R. J. Metabolic pathways promoting cancer cell survival and growth. Nat. Cell Biol. 17, 351–359 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Chae, Y. K. et al. Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7, 40767–40780 (2016).

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Kasznicki, J., Sliwinska, A. & Drzewoski, J. Metformin in cancer prevention and therapy. Ann. Transl Med. 2, 57 (2014).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Wheaton, W. W. et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 3, e02242 (2014).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    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).

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Duan, W. et al. Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression. Cancer Lett. 385, 225–233 (2017).

    CAS  PubMed  Google Scholar 

  150. 150.

    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).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Chen, K. et al. Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer. Mol. Cancer 16, 131 (2017).

    PubMed  PubMed Central  Google Scholar 

  152. 152.

    Weinberg, S. E. & Chandel, N. S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9–15 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Griss, T. et al. Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLOS Biol. 13, e1002309 (2015).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    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).

    CAS  PubMed  Google Scholar 

  156. 156.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    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.

    CAS  PubMed  Google Scholar 

  158. 158.

    Wang, T. et al. Synthesis of improved lysomotropic autophagy inhibitors. J. Med. Chem. 58, 3025–3035 (2015).

    CAS  PubMed  Google Scholar 

  159. 159.

    Rebecca, V. W. et al. A unified approach to targeting the lysosome’s degradative and growth signaling roles. Cancer Discov. 7, 1266–1283 (2017).

    CAS  PubMed  Google Scholar 

  160. 160.

    Sui, X. et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 4, e838 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Muranen, T. et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21, 227–239 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Huang, C. et al. β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res. 13, R84 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    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).

    CAS  PubMed  Google Scholar 

  165. 165.

    Yang, A. et al. Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms. Cancer Discov. 8, 276–287 (2018).

    CAS  PubMed  Google Scholar 

  166. 166.

    Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    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).

    CAS  Google Scholar 

  168. 168.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    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).

    CAS  PubMed  Google Scholar 

  170. 170.

    Cai, Q., Yan, L. & Xu, Y. Anoikis resistance is a critical feature of highly aggressive ovarian cancer cells. Oncogene 34, 3315–3324 (2015).

    CAS  PubMed  Google Scholar 

  171. 171.

    Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    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).

    CAS  PubMed  Google Scholar 

  174. 174.

    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).

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    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).

    PubMed  PubMed Central  Google Scholar 

  176. 176.

    Méresse, S. et al. Controlling the maturation of pathogen-containing vacuoles: a matter of life and death. Nat. Cell Biol. 1, E183–E188 (1999).

    PubMed  PubMed Central  Google Scholar 

  177. 177.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Schaefer, L. Complexity of danger: the diverse nature of damage-associated molecular patterns. J. Biol. Chem. 289, 35237–35245 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Zhao, W., Qiu, Y. & Kong, D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm. Sin. B 7, 27–37 (2017).

    PubMed  PubMed Central  Google Scholar 

  180. 180.

    Massacesi, C. et al. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design. Onco Targets Ther. 9, 203–210 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Janku, F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients. Cancer Treat. Rev. 59, 93–101 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    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).

    PubMed  PubMed Central  Google Scholar 

  183. 183.

    Okada, T. et al. Integrin-α10 dependency identifies RAC and RICTOR as therapeutic targets in high-grade myxofibrosarcoma. Cancer Discov. 6, 1148–1165 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Yeo, D. et al. FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. BMC Cancer 16, 24 (2016).

    PubMed  PubMed Central  Google Scholar 

  186. 186.

    Dai, R. Y. et al. Implication of transcriptional repression in compound C-induced apoptosis in cancer cells. Cell Death Dis. 4, e883 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Ohta, T. et al. Bafilomycin A1 induces apoptosis in the human pancreatic cancer cell line Capan-1. J. Pathol. 185, 324–330 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Kitazawa, S. et al. Cancer with low cathepsin D levels is susceptible to vacuolar (H+)-ATPase inhibition. Cancer Sci. 108, 1185–1193 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

A.L.E. was supported by grants from the Congressionally Directed Medical Research Programs (CDMRP) (W81XWH-15-1-0010), the University of California Cancer Research Coordinating Committee (CRR-17-426826), University of California Irvine (UCI) Applied Innovation and the UCI Chao Family Comprehensive Cancer Center Anti-Cancer Challenge. The authors thank the referees for the peer review of this work.

Reviewer information

Nature Reviews Cancer thanks J. Swanson, A. Thorburn and the anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Affiliations

Authors

Contributions

All authors contributed to substantial discussions, research and collection of references and the writing and editing of the article. B.T.F. and A.L.E. organized and planned the display figures and boxes.

Corresponding author

Correspondence to Aimee L. Edinger.

Ethics declarations

Competing interests

A.L.E. is listed as an inventor on a patent covering the synthesis of SH-BC-893 and its use as a treatment for cancer and other diseases.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Desmoplasia

A process by which dense stromal cells extensively deposit extracellular matrix proteins, increasing interstitial pressure and decreasing vascular perfusion.

Anabolism

The biosynthetic processes that assembles nutrients into macromolecules that contribute to cellular biomass.

Nutrient scavenging

The removal and breakdown of macromolecules from the microenvironment into components that can be used for ATP production and/or anabolism.

Recycling

The catabolism of a cell’s own macromolecules into subunits that are used to fuel ATP production or to synthesize new polymers; autophagy is a recycling process.

Cell-autonomous growth

Cellular growth (both biosynthesis and proliferation) that does not depend on building blocks produced by other cells.

Collagen

The most abundant structural protein in the ECM.

Laminin

A high molecular weight heterotrimeric glycoprotein that forms the basement membrane that facilitates cell adhesion and tissue structural maintenance.

Fibronectin

A high-molecular-mass protein dimer that binds cell membrane integrin receptors and neighbouring extracellular matrix proteins like collagen to facilitate cell adhesion.

Integrins

Heterodimeric receptors that facilitate cell adhesion to extracellular matrix (ECM) and coordinate diverse signalling processes. Internalization of integrins allows scavenging of ECM components.

Anoikis

A form of programmed cell death induced by detachment of anchorage-dependent cells from the extracellular matrix; metastatic tumour cells escape death by anoikis and become anchorage-independent.

Albumin

The most abundant serum protein; albumin facilitates transport of solutes (fatty acids, vitamins, metal ions, and so on) throughout the body.

Macropinocytosis

A non-selective form of endocytosis by which cells assimilate both extracellular fluid and macromolecules by generating large, uncoated endocytic vesicles (macropinosomes) that range in diameter from 0.2 to 5.0 μm.

Macropinocytic flux

The rate at which macropinocytosed macromolecules are converted into nutrients that are exported to the cytosol; variables contributing to the rate of flux include uptake, evasion of endocytic recycling, catabolism to monomers in lysosomes and release into the cytosol.

Na+/H+ exchanger

(NHE). Plasma membrane protein that promotes exchange of protons for sodium ions; NHE proteins play a key role in maintaining cellular pH.

Necrotic cell debris

Physical remnants of cells that have died from a metabolic crisis or fragmented following apoptosis (secondary necrosis).

Exosomes

Small cell-derived vesicles released into the microenvironment that can contain metabolic intermediates, sugars, RNAs (for example, microRNAs), DNA and intact proteins.

Entosis

The invasion of a living cell into another cell; engulfed ‘loser’ cells can either escape back to the microenvironment or be degraded and provide nutrients to the ‘winner’ cell.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Finicle, B.T., Jayashankar, V. & Edinger, A.L. Nutrient scavenging in cancer. Nat Rev Cancer 18, 619–633 (2018). https://doi.org/10.1038/s41568-018-0048-x

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing