Autophagy is a major metabolic regulator involved in cancer therapy resistance

Autophagy sustains cellular homeostasis and metabolism in numerous diseases. By regulating cancer metabolism, both tumor and microenvironmental autophagy promote tumor growth. However, autophagy can support cancer progression through other biological functions such as immune response regulation or cytokine/growth factor secretion. Moreover, autophagy is induced in numerous tumor types as a resistance mechanism following therapy, highlighting autophagy inhibition as a promising target for anti-cancer therapy. Thus, better understanding the mechanisms involved in tumor growth and resistance regulation through autophagy, which are not fully understood, will provide insights into patient treatment. Autophagy sustains cellular homeostasis and metabolism in numerous diseases. By regulating cancer metabolism, both tumor and microenvironmental autophagy promote tumor growth. However, autophagy can support cancer progression through other biological functions such as immune response regulation or cytokine/growth factor secretion. Moreover, autophagy is induced in numerous tumor types as a resistance mechanism following therapy, highlighting autophagy inhibition as a promising target for anti-cancer therapy. Thus, better understanding the mechanisms involved in tumor growth and resistance regulation through autophagy, which are not fully understood, will provide insights into patient treatment. The term autophagy, from the Greek meaning "self-eating," was coined in 1963 by Christian De Duve who discovered this mechanism while working on lysosomes. Since then, autophagy has been studied by many laboratories, first for its regulation of nutrient availability and role in cytotoxic stress and starvation and then for its involvement in health and disease such as neurodegenerative diseases, infectious diseases, diabetes, and cancer (Yang and Klionsky, 2020Yang Y. Klionsky D.J. Autophagy and disease: unanswered questions.Cell Death Differ. 2020; 27: 858-871Crossref PubMed Scopus (83) Google Scholar). The role of autophagy is complex in cancer because autophagy has both tumor-promoting and tumor-inhibiting functions depending on the tumor stage (White, 2015White E. The role for autophagy in cancer.J. Clin. Invest. 2015; 125: 42-46Crossref PubMed Scopus (693) Google Scholar). To date, most studies have focused on the role of cell autonomous autophagy in cancer (tumor autophagy), referring to autophagy occurring within the tumor cells. More recently, the role of non-cell autonomous autophagy (host autophagy), that is induced within the tumor microenvironment or in distant tissues, has become of great interest in cancer biology. In addition to its role in tumor growth, autophagy can regulate cancer therapy efficacy and resistance, suggesting autophagy inhibition can be leveraged for combination therapy. In this review, we will focus on the current knowledge and remaining questions regarding the role of tumor and host autophagy in metabolism and resistance to therapy of solid tumors and leukemias. Autophagy is a catabolic process involved in the degradation and recycling of cytoplasmic components and damaged proteins/organelles. There are three forms of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) (Parzych and Klionsky, 2014Parzych K.R. Klionsky D.J. An overview of autophagy: morphology, mechanism, and regulation.Antioxid. Redox Signal. 2014; 20: 460-473Crossref PubMed Scopus (763) Google Scholar). Macroautophagy (hereafter called autophagy) is the most studied form of autophagy and the topic of this review. It is regulated by more than 40 autophagy-related genes (Atg) and characterized by the sequestration of the cargo into a double-membrane vesicle called autophagosome that fuses with a lysosome to form an autophagolysosome. The content of the autophagolysosome is then degraded and recycled into amino acids (aas), nucleic acids, and fatty acids that can be used to support metabolism (Mizushima and Klionsky, 2007Mizushima N. Klionsky D.J. Protein turnover via autophagy: implications for metabolism.Annu. Rev. Nutr. 2007; 27: 19-40Crossref PubMed Scopus (559) Google Scholar). Microautophagy and CMA do not require autophagosome vesicle formation. Microautophagy is characterized by the direct engulfment of cytoplasmic components into the lysosome for their degradation in either a non-selective or selective way. CMA only allows selective targeting and delivery of proteins harboring the KFERQ motif to the lysosome upon recognition by the chaperone HSC-70 (Tekirdag and Cuervo, 2018Tekirdag K. Cuervo A.M. Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone.J. Biol. Chem. 2018; 293: 5414-5424Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Basal autophagy is utilized to maintain cellular homeostasis but can also be induced following different stresses such as nutrient starvation, oxidative stress, disease states, or infection to allow cell survival (Komatsu et al., 2005Komatsu M. Waguri S. Ueno T. Iwata J. Murata S. Tanida I. Ezaki J. Mizushima N. Ohsumi Y. Uchiyama Y. et al.Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.J. Cell Biol. 2005; 169: 425-434Crossref PubMed Scopus (1739) Google Scholar). Although the main function of non-selective or bulk autophagy is to help cells to survive during crisis, autophagy can also be selective by identifying and targeting specific cargos for degradation and sustain cellular homeostasis. In fact, autophagy can selectively degrade specific cargos such as mitochondria, peroxisomes, protein aggregates, or bacteria through mechanisms called mitophagy, pexophagy, aggrephagy, or xenophagy, respectively (Gatica et al., 2018Gatica D. Lahiri V. Klionsky D.J. Cargo recognition and degradation by selective autophagy.Nat. Cell Biol. 2018; 20: 233-242Crossref PubMed Scopus (338) Google Scholar). To do so, specific substrates are targeted and bound to autophagy receptors such as p62/sequestosome 1 (SQSTM1), neighbor of BRCA1 gene 1 (NBR1), or NIX. These autophagy receptors, once bound to the cargo, will then directly interact with the ubiquitin-like family proteins microtubule-associated protein 1A/1B-light chain 3 (LC3) and GABA receptor-associated proteins (GABARAPs) located at the autophagosome through a 15–20 aa long sequence called LC3-interacting regions (LIRs) motif (Kirkin and Rogov, 2019Kirkin V. Rogov V.V. A Diversity of Selective Autophagy Receptors Determines the Specificity of the Autophagy Pathway.Mol. Cell. 2019; 76: 268-285Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) to allow their engulfment and their degradation through autophagy. Through degradation and recycling of organelles or cytoplasmic components, autophagy is able to either eliminate substrates to regulate metabolism or to provide substrates to feed metabolic pathways (Mizushima and Klionsky, 2007Mizushima N. Klionsky D.J. Protein turnover via autophagy: implications for metabolism.Annu. Rev. Nutr. 2007; 27: 19-40Crossref PubMed Scopus (559) Google Scholar; Rabinowitz and White, 2010Rabinowitz J.D. White E. Autophagy and metabolism.Science. 2010; 330: 1344-1348Crossref PubMed Scopus (1261) Google Scholar). Degradation of proteins, organelles, and cytoplasmic components by autophagy produces different substrates such as aas, fatty acids, sugars, and nucleosides that are catabolized by the pentose phosphate pathway (PPP), glycolysis, or TCA cycle (Rabinowitz and White, 2010Rabinowitz J.D. White E. Autophagy and metabolism.Science. 2010; 330: 1344-1348Crossref PubMed Scopus (1261) Google Scholar). For example, aas produced from protein breakdown can be used as substrate for ATP production, de novo protein synthesis, or gluconeogenesis regulation (Lum et al., 2005Lum J.J. Bauer D.E. Kong M. Harris M.H. Li C. Lindsten T. Thompson C.B. Growth factor regulation of autophagy and cell survival in the absence of apoptosis.Cell. 2005; 120: 237-248Abstract Full Text Full Text PDF PubMed Scopus (1205) Google Scholar; Onodera and Ohsumi, 2005Onodera J. Ohsumi Y. Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation.J. Biol. Chem. 2005; 280: 31582-31586Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar; Ezaki et al., 2011Ezaki J. Matsumoto N. Takeda-Ezaki M. Komatsu M. Takahashi K. Hiraoka Y. Taka H. Fujimura T. Takehana K. Yoshida M. et al.Liver autophagy contributes to the maintenance of blood glucose and amino acid levels.Autophagy. 2011; 7: 727-736Crossref PubMed Scopus (174) Google Scholar). In addition to aas, autophagy can directly regulate gluconeogenesis through degradation of glycogen (Jiang et al., 2010Jiang S. Heller B. Tagliabracci V.S. Zhai L. Irimia J.M. DePaoli-Roach A.A. Wells C.D. Skurat A.V. Roach P.J. Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism.J. Biol. Chem. 2010; 285: 34960-34971Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Autophagy also regulates lipid metabolism by degrading lipid droplets through lipophagy contributing to the generation of free fatty acids (FFAs), which are oxidized by mitochondria (Singh et al., 2009Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. Tanaka K. Cuervo A.M. Czaja M.J. Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2220) Google Scholar; Skop et al., 2012Skop V. Cahová M. Papáčková Z. Páleníčková E. Daňková H. Baranowski M. Zabielski P. Zdychová J. Zídková J. Kazdová L. Autophagy-lysosomal pathway is involved in lipid degradation in rat liver.Physiol. Res. 2012; 61: 287-297Crossref PubMed Google Scholar). Moreover, mitophagy that allows specific degradation of mitochondria, the "powerhouse" of cell metabolism, is increased in metabolically active tissues to meet energy demands (McWilliams et al., 2018McWilliams T.G. Prescott A.R. Montava-Garriga L. Ball G. Singh F. Barini E. Muqit M.M.K. Brooks S.P. Ganley I.G. Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand.Cell Metab. 2018; 27: 439-449.e5Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). Consistent with these data, mice with constitutive loss of Atg5 or Atg7, two important autophagy genes, are born developmentally normal but fail to survive the neonatal period due to metabolic insufficiency (Komatsu et al., 2005Komatsu M. Waguri S. Ueno T. Iwata J. Murata S. Tanida I. Ezaki J. Mizushima N. Ohsumi Y. Uchiyama Y. et al.Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.J. Cell Biol. 2005; 169: 425-434Crossref PubMed Scopus (1739) Google Scholar; Kuma et al., 2004Kuma A. Hatano M. Matsui M. Yamamoto A. Nakaya H. Yoshimori T. Ohsumi Y. Tokuhisa T. Mizushima N. The role of autophagy during the early neonatal starvation period.Nature. 2004; 432: 1032-1036Crossref PubMed Scopus (2216) Google Scholar). On the other hand, mice with acute systemic loss of Atg7 survive up to 3 months of age but display depletion of lipid and glycogen stores, defects in FFA mobilization, muscle wasting, liver damage, and neurodegenerative defects (Karsli-Uzunbas et al., 2014Karsli-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. White E. Autophagy is required for glucose homeostasis and lung tumor maintenance.Cancer Discov. 2014; 4: 914-927Crossref PubMed Scopus (301) Google Scholar). Systemic loss of Atg7 also converts white adipose tissue to brown adipose tissue, a mitochondria-rich tissue that catabolizes glucose and lipids to generate heat rather than ATP. These mice are not able to survive starvation due to fatal hypoglycemia (Karsli-Uzunbas et al., 2014Karsli-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. White E. Autophagy is required for glucose homeostasis and lung tumor maintenance.Cancer Discov. 2014; 4: 914-927Crossref PubMed Scopus (301) Google Scholar). Therefore, although metabolic status can regulate autophagy, autophagy itself has an important role in metabolism regulation. Altogether, these data and those from others demonstrate the important role of autophagy in cellular and mammalian metabolism. In this review, we will focus on the recent breakthroughs regarding the functions of autophagy in cancer progression mainly through its role in metabolism. Given the role of autophagy in supporting metabolism, it is not surprising that its deregulation is involved in numerous diseases such as metabolic diseases, neurodegenerative diseases, infectious diseases, and cancer (Mizushima et al., 2008Mizushima N. Levine B. Cuervo A.M. Klionsky D.J. Autophagy fights disease through cellular self-digestion.Nature. 2008; 451: 1069-1075Crossref PubMed Scopus (4643) Google Scholar; Choi et al., 2013Choi A.M. Ryter S.W. Levine B. Autophagy in human health and disease.N. Engl. J. Med. 2013; 368: 1845-1846Crossref PubMed Scopus (791) Google Scholar). Autophagy was first identified as a tumor suppressor mechanism as numerous Atg genes were downregulated in tumors. The first gene to be identified as such was Beclin-1, which is mono-allelically deleted in breast, ovarian, and pancreatic cancer (Liang et al., 1999Liang X.H. Jackson S. Seaman M. Brown K. Kempkes B. Hibshoosh H. Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1.Nature. 1999; 402: 672-676Crossref PubMed Scopus (2526) Google Scholar). Moreover, disruption of Beclin-1 increases the frequency of spontaneous tumors, increased proliferation, and decreased autophagy in vivo, confirming the tumor suppressor role of autophagy (Qu et al., 2003Qu X. Yu J. Bhagat G. Furuya N. Hibshoosh H. Troxel A. Rosen J. Eskelinen E.L. Mizushima N. Ohsumi Y. et al.Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.J. Clin. Invest. 2003; 112: 1809-1820Crossref PubMed Scopus (1688) Google Scholar). Frameshift mutation of several other Atg genes, such as Atg2b, Atg5, Atg9b, and Atg12, is observed in human cancer where it may contribute to tumorigenesis (Kang et al., 2009Kang M.R. Kim M.S. Oh J.E. Kim Y.R. Song S.Y. Kim S.S. Ahn C.H. Yoo N.J. Lee S.H. Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability.J. Pathol. 2009; 217: 702-706Crossref PubMed Scopus (162) Google Scholar). Despite this evidence, it is now clear that the role of autophagy in cancer is more complex, and autophagy can have opposing effects in cancer depending on the tumor type, genetic and epigenetic status, tumor stage, and context (White, 2012White E. Deconvoluting the context-dependent role for autophagy in cancer.Nat. Rev. Cancer. 2012; 12: 401-410Crossref PubMed Scopus (1078) Google Scholar). On one hand, autophagy can act as a tumor suppressor during the early stages of tumorigenesis by eliminating reactive oxygen species (ROS), DNA damage, and inflammation, which are known inducers of tumor initiation (Karantza-Wadsworth et al., 2007Karantza-Wadsworth V. Patel S. Kravchuk O. Chen G. Mathew R. Jin S. White E. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis.Genes Dev. 2007; 21: 1621-1635Crossref PubMed Scopus (624) Google Scholar; Mathew et al., 2007Mathew R. Kongara S. Beaudoin B. Karp C.M. Bray K. Degenhardt K. Chen G. Jin S. White E. Autophagy suppresses tumor progression by limiting chromosomal instability.Genes Dev. 2007; 21: 1367-1381Crossref PubMed Scopus (692) Google Scholar; Deretic et al., 2013Deretic V. Saitoh T. Akira S. Autophagy in infection, inflammation and immunity.Nat. Rev. Immunol. 2013; 13: 722-737Crossref PubMed Scopus (1113) Google Scholar). Thus, deletion of Atg5 or Atg7 in the pancreas or liver leads to the development of benign tumors: pancreatic intraepithelial neoplasia (PANIN) and spontaneous liver adenomas, respectively, that never progress to a malignant tumor (Takamura et al., 2011Takamura A. Komatsu M. Hara T. Sakamoto A. Kishi C. Waguri S. Eishi Y. Hino O. Tanaka K. Mizushima N. Autophagy-deficient mice develop multiple liver tumors.Genes Dev. 2011; 25: 795-800Crossref PubMed Scopus (801) Google Scholar; Rosenfeldt et al., 2013Rosenfeldt M.T. O'Prey J. Morton J.P. Nixon C. MacKay G. Mrowinska A. Au A. Rai T.S. Zheng L. Ridgway R. et al.p53 status determines the role of autophagy in pancreatic tumour development.Nature. 2013; 504: 296-300Crossref PubMed Scopus (443) Google Scholar; Yang et al., 2014Yang A. Rajeshkumar N.V. Wang X. Yabuuchi S. Alexander B.M. Chu G.C. Von Hoff D.D. Maitra A. Kimmelman A.C. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.Cancer Discov. 2014; 4: 905-913Crossref PubMed Scopus (274) Google Scholar). These data indicate that even though lack of autophagy can increase tumor initiation, autophagy is still required for tumors to progress to malignancy. On the other hand, autophagy can support tumor growth. This is the case upon the deletion of Atg5 or Atg7 in melanoma, lung, prostate, and pancreatic cancer cells that led to a decrease in tumor progression (Karsli-Uzunbas et al., 2014Karsli-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. White E. Autophagy is required for glucose homeostasis and lung tumor maintenance.Cancer Discov. 2014; 4: 914-927Crossref PubMed Scopus (301) Google Scholar; Yang et al., 2014Yang A. Rajeshkumar N.V. Wang X. Yabuuchi S. Alexander B.M. Chu G.C. Von Hoff D.D. Maitra A. Kimmelman A.C. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.Cancer Discov. 2014; 4: 905-913Crossref PubMed Scopus (274) Google Scholar; Guo et al., 2013Guo J.Y. Karsli-Uzunbas G. Mathew R. Aisner S.C. Kamphorst J.J. Strohecker A.M. Chen G. Price S. Lu W. Teng X. et al.Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis.Genes Dev. 2013; 27: 1447-1461Crossref PubMed Scopus (379) Google Scholar; Strohecker et al., 2013Strohecker A.M. Guo J.Y. Karsli-Uzunbas G. Price S.M. Chen G.J. Mathew R. McMahon M. White E. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors.Cancer Discov. 2013; 3: 1272-1285Crossref PubMed Scopus (262) Google Scholar; Xie et al., 2015Xie X. Koh J.Y. Price S. White E. Mehnert J.M. Atg7 Overcomes Senescence and Promotes Growth of BrafV600E-Driven Melanoma.Cancer Discov. 2015; 5: 410-423Crossref PubMed Scopus (116) Google Scholar; Santanam et al., 2016Santanam U. Banach-Petrosky W. Abate-Shen C. Shen M.M. White E. DiPaola R.S. Atg7 cooperates with Pten loss to drive prostate cancer tumor growth.Genes Dev. 2016; 30: 399-407Crossref PubMed Google Scholar). The role of autophagy in cancer can also vary depending on the genetic context. In fact, in a model of pancreatic ductal adenocarcinoma (PDAC), deletion of Atg5 or Atg7, in the presence of p53, inhibits the formation of malignant pancreatic tumors whereas loss of autophagy accelerates tumor growth in the absence of p53 (Rosenfeldt et al., 2013Rosenfeldt M.T. O'Prey J. Morton J.P. Nixon C. MacKay G. Mrowinska A. Au A. Rai T.S. Zheng L. Ridgway R. et al.p53 status determines the role of autophagy in pancreatic tumour development.Nature. 2013; 504: 296-300Crossref PubMed Scopus (443) Google Scholar). Consistently, in Kras-driven lung cancer, Atg7 deletion induces p53 and reduces tumor burden, which was rescued by p53 loss (Guo et al., 2013Guo J.Y. Karsli-Uzunbas G. Mathew R. Aisner S.C. Kamphorst J.J. Strohecker A.M. Chen G. Price S. Lu W. Teng X. et al.Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis.Genes Dev. 2013; 27: 1447-1461Crossref PubMed Scopus (379) Google Scholar). However, in Braf-driven lung cancer, although p53 induction by Atg7 deficiency also contributed to growth arrest, p53 deletion did not affect Atg7−/− tumor growth (Strohecker et al., 2013Strohecker A.M. Guo J.Y. Karsli-Uzunbas G. Price S.M. Chen G.J. Mathew R. McMahon M. White E. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors.Cancer Discov. 2013; 3: 1272-1285Crossref PubMed Scopus (262) Google Scholar). Altogether, these data highlight the importance of the genetic context (here, p53 status) and tumor type when studying the role of autophagy in cancer. Although the role of autophagy in promoting tumor growth is multifaceted, it is important to understand how autophagy impacts tumorigenesis. One of the hallmarks of cancer is the capacity to rewire metabolism to meet biosynthetic, redox, and bioenergetic needs required for cancer growth and proliferation. The first metabolic reprogramming to be described in cancer cells was the "Warburg effect" or aerobic glycolysis, characterized by an increased glucose uptake and increased lactate secretion even in the presence of oxygen (Warburg, 1956Warburg O. On the origin of cancer cells.Science. 1956; 123: 309-314Crossref PubMed Google Scholar; Vander Heiden et al., 2009Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (8476) Google Scholar). Although glucose is the major contributor to cancer metabolism, aas (like glutamine or arginine and fatty acids) are also required for tumor growth. Thus, in addition to glycolysis, other metabolic pathways such as fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) are highly reprogrammed in cancer cells (Yang et al., 2017Yang L. Venneti S. Nagrath D. Glutaminolysis: A Hallmark of Cancer Metabolism.Annu. Rev. Biomed. Eng. 2017; 19: 163-194Crossref PubMed Scopus (190) Google Scholar; Röhrig and Schulze, 2016Röhrig F. Schulze A. The multifaceted roles of fatty acid synthesis in cancer.Nat. Rev. Cancer. 2016; 16: 732-749Crossref PubMed Scopus (427) Google Scholar; Ashton et al., 2018Ashton T.M. McKenna W.G. Kunz-Schughart L.A. Higgins G.S. Oxidative Phosphorylation as an Emerging Target in Cancer Therapy.Clin. Cancer Res. 2018; 24: 2482-2490Crossref PubMed Scopus (223) Google Scholar). In order to reprogram their metabolism, cancer cells can use the autophagy pathway, which is increased in numerous cancer cells compared to normal cells. In fact, autophagy is upregulated in tumor regions experiencing metabolic stress and is essential for tumor survival (Degenhardt et al., 2006Degenhardt K. Mathew R. Beaudoin B. Bray K. Anderson D. Chen G. Mukherjee C. Shi Y. Gélinas C. Fan Y. et al.Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis.Cancer Cell. 2006; 10: 51-64Abstract Full Text Full Text PDF PubMed Scopus (1452) Google Scholar). For example, Ras mutation upregulates autophagy in cancer cells allowing their survival upon starvation, tumorigenesis, and transformation. This increased autophagy was shown to support either increased mitochondrial oxidative metabolism or glycolysis depending on tumor type (Guo et al., 2011Guo J.Y. Chen H.Y. Mathew R. Fan J. Strohecker A.M. Karsli-Uzunbas G. Kamphorst J.J. Chen G. Lemons J.M. Karantza V. et al.Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis.Genes Dev. 2011; 25: 460-470Crossref PubMed Scopus (829) Google Scholar; Lock et al., 2011Lock R. Roy S. Kenific C.M. Su J.S. Salas E. Ronen S.M. Debnath J. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation.Mol. Biol. Cell. 2011; 22: 165-178Crossref PubMed Scopus (322) Google Scholar; Yang et al., 2011Yang S. Wang X. Contino G. Liesa M. Sahin E. Ying H. Bause A. Li Y. Stommel J.M. Dell'antonio G. et al.Pancreatic cancers require autophagy for tumor growth.Genes Dev. 2011; 25: 717-729Crossref PubMed Scopus (899) Google Scholar). For example, defective autophagy leads to abnormal mitochondria accumulation, reduces oxygen consumption, and causes depletion of TCA cycle intermediates and energy during starvation in Ras-mutated lung cancer (Guo et al., 2011Guo J.Y. Chen H.Y. Mathew R. Fan J. Strohecker A.M. Karsli-Uzunbas G. Kamphorst J.J. Chen G. Lemons J.M. Karantza V. et al.Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis.Genes Dev. 2011; 25: 460-470Crossref PubMed Scopus (829) Google Scholar). Similarly, autophagy is necessary to regulate glycolysis required for tumor growth in polyoma middle T antigen-driven breast cancer and chronic myeloid leukemia (CML) (Wei et al., 2011Wei H. Wei S. Gan B. Peng X. Zou W. Guan J.L. Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis.Genes Dev. 2011; 25: 1510-1527Crossref PubMed Scopus (238) Google Scholar; Karvela et al., 2016Karvela M. Baquero P. Kuntz E.M. Mukhopadhyay A. Mitchell R. Allan E.K. Chan E. Kranc K.R. Calabretta B. Salomoni P. et al.ATG7 regulates energy metabolism, differentiation and survival of Philadelphia-chromosome-positive cells.Autophagy. 2016; 12: 936-948Crossref PubMed Google Scholar). Autophagy is upregulated in FLT3-ITD and c-Kit mutants AML, which is required for cell proliferation and survival in vitro and in vivo (Heydt et al., 2018Heydt Q. Larrue C. Saland E. Bertoli S. Sarry J.E. Besson A. Manenti S. Joffre C. Mansat-De Mas V. Oncogenic FLT3-ITD supports autophagy via ATF4 in acute myeloid leukemia.Oncogene. 2018; 37: 787-797Crossref PubMed Scopus (37) Google Scholar; Larrue et al., 2019Larrue C. Heydt Q. Saland E. Boutzen H. Kaoma T. Sarry J.E. Joffre C. Récher C. Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia.Oncogenesis. 2019; 8: 39Crossref PubMed Scopus (11) Google Scholar). Mechanistically, mitochondria through mitochondria- endoplasmic reticulum (ER) contact sites control autophagy that in turn regulates lipid metabolism to fuel mitochondrial metabolism allowing AML cell growth (Bosc et al., 2020Bosc C. Broin N. Fanjul M. Saland E. Farge T. Courdy C. Batut A. Masoud R. Larrue C. Skuli S. et al.Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites.Nat. Commun. 2020; 11: 4056Crossref PubMed Scopus (19) Google Scholar). In addition, it has been shown that mammalian target of rapamycin complex 1 (mTORC1), an autophagy regulator, controls glucose dependency of AML cells to sustain high PPP (Poulain et al., 2017Poulain L. Sujobert P. Zylbersztejn F. Barreau S. Stuani L. Lambert M. Palama T.L. Chesnais V. Birsen R. Vergez F. et al.High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells.Leukemia. 2017; 31: 2326-2335Crossref PubMed Scopus (41) Google Scholar). These works demonstrate that autophagy is able to modulate tumor cell metabolism. The development of genetically engineered mouse models (GEMMs) for cancer and autophagy deficiency have provided a powerful tool to better understand and confirm the role of autophagy in cancer metabolism. Using these GEMMs, it has been demonstrated that autophagy modulates tumor cell metabolism to promote the growth of lung, melanoma, PDAC, and prostate cancers that arise from KrasG12D, BrafV600E, Pten−/−, or Lkb1−/− mutations (Karsli-Uzunbas et al., 2014Karsli-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. White E. Autophagy is required for glucose homeostasis and lung tumor maintenance.Cancer Discov. 2014; 4: 914-927Crossref PubMed Scopus (301) Google Scholar; Yang et al., 2014Yang A. Rajeshkumar N.V. Wang X. Yabuuchi S. Alexander B.M. Chu G.C. Von Hoff D.D. Maitra A. Kimmelman A.C. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.Cancer Discov. 2014; 4: 905-913Crossref PubMed Scopus (274) Google Scholar; Guo et al., 2013Guo J.Y. Karsli-Uzunbas G. Mathew R. Aisner S.C. Kamphorst J.J. Strohecker A.M. Chen G. Price S. Lu W. Teng X. et al.Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis.Genes Dev. 2013; 27: 1447-1461Crossref PubMed Scopus (379) Google Scholar; Strohecker et al., 2013Strohecker A.M. Guo J.Y. Karsli-Uzunbas G. Price S.M. Chen G.J. Mathew R. McMahon M. White E. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors.Cancer Discov. 2013; 3: 1272-1285Crossref PubMed Scopus (262) Google Scholar; Xie et al., 2015Xie X. Koh J.Y. Price S. White E. Mehnert J.M. Atg7 Overcomes Senescence and Promotes Growth of BrafV600E-Driven Melanoma.Cancer Discov. 2015; 5: 410-423Crossref PubMed Scopus (116) Google Scholar, Santanam et al., 2016Santanam U. Banach-Petrosky W. Abate-Shen C. Shen M.M. White E. DiPaola R.S. Atg7 cooperates with Pten loss to drive prostate cancer tumor growth.Genes Dev. 2016; 30: 399-407Crossref PubMed Google Scholar; Bhatt et al., 2019Bhatt V. Khayati K. Hu Z.S. Lee A. Kamran W. Su X. Guo J.Y. Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis.Genes Dev. 2019; 33: 150-165Crossref PubMed Scopus (34) Google Scholar). Indeed, in lung cancer, loss of Atg7 leads to an accumulation of damaged mitochondria and to a defective FAO in the absence of p53, associated with tumor burden reduction (Guo et al., 2013Guo J.Y. Karsli-Uzunbas G. Mathew R. Aisner S.C. Kamphorst J.J. Strohecker A.M. Chen G. Price S. Lu W. Teng X. et al.Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis.Genes Dev. 2013; 27: 1447-1461Crossref PubMed Scopus (379) Google Scholar; Strohecker et al., 2013Strohecker A.M. Guo J.Y. Karsli-Uzunbas G. Price S.M. Chen G.J. Mathew R. McMahon M. White E. Autophagy sustains mitochondrial glutamine metabolism and gro