Role of Autophagy in Cancer

Summary

Principal Investigator: Eileen White
Abstract: DESCRIPTION (provided by applicant): Cells capture intracellular proteins and organelles by the process of macroautophagy (autophagy hereafter), which delivers them to lysosomes where they are degraded. The breakdown products of autophagy cargo such as amino acids, sugars, nucleosides and lipids, are released from lysosomes into the cytoplasm where they are reused. Autophagy thereby recycles intracellular components to sustain cell and organism metabolism and survival in starvation, a function conserved from yeast to mammals. Autophagy is also a mechanism for eliminating cellular waste such as damaged proteins and organelles, particularly mitochondria, the accumulation of which is toxic. This protein and organelle quality control function of autophagy is also highly conserved and required for homeostasis. Autophagy levels are normally low, but are dramatically induced by starvation and stress to facilitate cellular adaptation. Cancer cells also rely on autophagy, but more so than normal cells. This may be due to high metabolic demand imposed by cancer cell growth and residence in a stressful microenvironment. In contrast to normal cells, cancer cells often have autophagy induced under fed conditions. For example, Ras-driven cancers commonly have high levels of basal autophagy and are extremely dependent on autophagy for sustaining mitochondrial respiration, for survival in stress and for tumorigenesis. Thus, in comparison to normal cells, some cancers may be addicted to autophagy and preferentially sensitive to autophagy inhibition, prompting interest in inhibiting autophagy to improve cancer therapy. Precisely how autophagy supports cancer growth and survival, the extent to which normal tissues and tumors are differentially affected, and the most effective means is to implement this concept in the clinic, remain open questions. To address these questions we examined the role of autophagy using genetically engineered mouse models (GEMMs) for K-rasG12D-driven non-small-cell lung cancer (NSCLC) and B-rafV600E- driven lung cancer. We found that deficiency in the essential autophagy gene atg7 causes tumor cells to accumulate large numbers of defective mitochondria and undergo atrophy. Atg7 deficiency also diverts progression of lung adenomas and carcinomas to oncocytomas. Oncocytomas are rare, predominantly benign neoplasms that arise in epithelial tissues that are characterized by the accumulation of large numbers of respiration-defective, mutant mitochondria. This discovery revealed for the first time that autophagy is a cancer fate determinant, that autophagy defects may be the molecular basis for the genesis of oncocytomas, and that oncocytomas can derive from adenomas and carcinomas when autophagy is impaired. We will test the central hypothesis that autophagy defects are the molecular basis for the genesis of oncocytomas. We will determine if atg7 deficiency produces mitochondrial genome mutations that convert carcinomas to oncocytomas, if mutations in essential autophagy genes cause human oncocytomas, and if producing oncocytomas by knocking out autophagy creates sensitivity to metabolic stress, enhancing cancer therapy.
Funding Period: 2007-12-01 - 2018-04-30
more information: NIH RePORT

Top Publications

  1. pmc Tumor suppression by autophagy through the management of metabolic stress
    Shengkan Jin
    Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA
    Autophagy 4:563-6. 2008
  2. pmc Liquid chromatography-high resolution mass spectrometry analysis of fatty acid metabolism
    Jurre J Kamphorst
    Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA
    Anal Chem 83:9114-22. 2011
  3. ncbi Autophagy, stress, and cancer metabolism: what doesn't kill you makes you stronger
    R Mathew
    The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
    Cold Spring Harb Symp Quant Biol 76:389-96. 2011
  4. pmc Deconvoluting the context-dependent role for autophagy in cancer
    Eileen White
    The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA
    Nat Rev Cancer 12:401-10. 2012
  5. pmc Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition
    Kevin Bray
    The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America
    PLoS ONE 7:e41831. 2012
  6. pmc Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis
    Jessie Yanxiang Guo
    The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
    Genes Dev 27:1447-61. 2013
  7. pmc Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors
    Anne M Strohecker
    1Cancer Institute of New Jersey, New Brunswick 2Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey and 3Department of Cellular and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California
    Cancer Discov 3:1272-85. 2013
  8. pmc Exploiting the bad eating habits of Ras-driven cancers
    Eileen White
    Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
    Genes Dev 27:2065-71. 2013
  9. pmc Autophagy-mediated tumor promotion
    Jessie Yanxiang Guo
    Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA
    Cell 155:1216-9. 2013
  10. ncbi Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism
    Anne M Strohecker
    Rutgers Cancer Institute of New Jersey New Brunswick, NJ USA Department of Molecular Biology and Biochemistry Rutgers University Piscataway, NJ USA
    Autophagy 10:384-5. 2014

Research Grants

Detail Information

Publications29

  1. pmc Tumor suppression by autophagy through the management of metabolic stress
    Shengkan Jin
    Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA
    Autophagy 4:563-6. 2008
    ..Furthermore, we need to be able to identify human tumors with deficient autophagy, and to develop rational cancer therapies that take advantage of the altered metabolic state and stress responses inherent to this autophagy defect...
  2. pmc Liquid chromatography-high resolution mass spectrometry analysis of fatty acid metabolism
    Jurre J Kamphorst
    Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA
    Anal Chem 83:9114-22. 2011
    ..This LC/MS method and associated isotope tracer techniques should be broadly applicable to investigating fatty acid metabolism...
  3. ncbi Autophagy, stress, and cancer metabolism: what doesn't kill you makes you stronger
    R Mathew
    The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
    Cold Spring Harb Symp Quant Biol 76:389-96. 2011
    ....
  4. pmc Deconvoluting the context-dependent role for autophagy in cancer
    Eileen White
    The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA
    Nat Rev Cancer 12:401-10. 2012
    ..Therefore, defining the context-specific role for autophagy in cancer and the mechanisms involved will be important to guide autophagy-based therapeutic intervention...
  5. pmc Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition
    Kevin Bray
    The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America
    PLoS ONE 7:e41831. 2012
    ..Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy...
  6. pmc Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis
    Jessie Yanxiang Guo
    The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
    Genes Dev 27:1447-61. 2013
    ..Moreover, cancers require autophagy for distinct roles in metabolism that are oncogene- and tumor suppressor gene-specific. ..
  7. pmc Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors
    Anne M Strohecker
    1Cancer Institute of New Jersey, New Brunswick 2Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey and 3Department of Cellular and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California
    Cancer Discov 3:1272-85. 2013
    ....
  8. pmc Exploiting the bad eating habits of Ras-driven cancers
    Eileen White
    Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
    Genes Dev 27:2065-71. 2013
    ..Targeting these distinct features of Ras-driven cancers provides novel approaches to cancer therapy. ..
  9. pmc Autophagy-mediated tumor promotion
    Jessie Yanxiang Guo
    Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA
    Cell 155:1216-9. 2013
    ..Autophagy promotes tumor growth by suppressing the p53 response, maintaining mitochondrial function, sustaining metabolic homeostasis and survival in stress, and preventing diversion of tumor progression to benign oncocytomas. ..
  10. ncbi Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism
    Anne M Strohecker
    Rutgers Cancer Institute of New Jersey New Brunswick, NJ USA Department of Molecular Biology and Biochemistry Rutgers University Piscataway, NJ USA
    Autophagy 10:384-5. 2014
    The role of autophagy in cancer is complex and context-dependent...
  11. pmc Mutational landscape of the essential autophagy gene BECN1 in human cancers
    Saurabh V Laddha
    Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903 2681
    Mol Cancer Res 12:485-90. 2014
    ..Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers...
  12. pmc Mode of action of diterpene and characterization of related metabolites from the soft coral, Xenia elongata
    Eric H Andrianasolo
    Center for Marine Biotechnology, Institute of Marine and Coastal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
    Mar Drugs 12:1102-15. 2014
    ..Compound (3) inhibits selectively HDAC6 in high micromolar concentrations. ..
  13. pmc Targeting mitochondrial metabolism by inhibiting autophagy in BRAF-driven cancers
    Anne M Strohecker
    Authors Affiliations Rutgers Cancer Institute of New Jersey, New Brunswick and
    Cancer Discov 4:766-72. 2014
    ..We suggest that combined inhibition of autophagy and BRAF may overcome this limitation...
  14. pmc Role of autophagy in cancer prevention
    Hsin Yi Chen
    The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
    Cancer Prev Res (Phila) 4:973-83. 2011
    ..These findings revealed the concept that aggressive cancers can be addicted to autophagy for survival. In this setting, autophagy inhibition is a therapeutic strategy for established cancers...
  15. pmc Principles and current strategies for targeting autophagy for cancer treatment
    Ravi K Amaravadi
    Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Clin Cancer Res 17:654-66. 2011
    ..Finally, we describe ongoing clinical trials involving HCQ as a first generation autophagy inhibitor, as well as strategies for the development of novel, more potent, and specific inhibitors of autophagy...
  16. pmc Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis
    Jessie Yanxiang Guo
    The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
    Genes Dev 25:460-70. 2011
    ..As cancers with Ras mutations have a poor prognosis, this "autophagy addiction" suggests that targeting autophagy and mitochondrial metabolism are valuable new approaches to treat these aggressive cancers...
  17. pmc A mouse mammary epithelial cell model to identify molecular mechanisms regulating breast cancer progression
    Vassiliki Karantza-Wadsworth
    Division of Medical Oncology, Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
    Methods Enzymol 446:61-76. 2008
    ....
  18. pmc Therapeutic starvation and autophagy in prostate cancer: a new paradigm for targeting metabolism in cancer therapy
    Robert S DiPaola
    Department of Medicine, University of Medicine and Dentistry of New Jersey UMDNJ Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
    Prostate 68:1743-52. 2008
    ..The understanding of autophagy, as either a mechanism of resistance to therapies that induce metabolic stress, or as a means to cell death, is rapidly expanding and supportive of a new paradigm of therapeutic starvation...
  19. pmc Assessing metabolic stress and autophagy status in epithelial tumors
    Robin Mathew
    University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
    Methods Enzymol 453:53-81. 2009
    ..Additionally these cell lines provide an efficient way to perform biochemical analyses, and high throughput screening for modulators of autophagy for potential use in cancer therapy and prevention...
  20. pmc Autophagy suppresses tumorigenesis through elimination of p62
    Robin Mathew
    University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
    Cell 137:1062-75. 2009
    ....
  21. pmc The double-edged sword of autophagy modulation in cancer
    Eileen White
    The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
    Clin Cancer Res 15:5308-16. 2009
    ..This is especially critical as many current cancer therapeutics activate autophagy. Therefore, efforts to understand and modulate the autophagy pathway will provide new approaches to cancer therapy and prevention...
  22. pmc Bcl-2 modulation to activate apoptosis in prostate cancer
    Kevin Bray
    The Cancer Institute of New Jersey, New Brunswick, NJ 08903 2681, USA
    Mol Cancer Res 7:1487-96. 2009
    ..Thus, rational targeting of both the Bcl-2 and Mcl-1 mechanisms of apoptosis resistance may be therapeutically advantageous for advanced prostate cancer...
  23. pmc Role of autophagy in suppression of inflammation and cancer
    Eileen White
    The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
    Curr Opin Cell Biol 22:212-7. 2010
    ..Thus, cellular damage mitigation through autophagy is a novel mechanism of tumor suppression...
  24. ncbi Ammonia derived from glutaminolysis is a diffusible regulator of autophagy
    Christina H Eng
    Center for Integrative Biology and Biotherapeutics, Pfizer, Pearl River, NY 10965, USA
    Sci Signal 3:ra31. 2010
    ..Thus, Gln metabolism not only fuels cell growth but also generates an autocrine- and paracrine-acting regulator of autophagic flux in proliferating cells...
  25. pmc Autophagy and metabolism
    Joshua D Rabinowitz
    Department of Chemistry and Lewis Sigler Institute for Integrative Genomics, 241 Carl Icahn Laboratory, Washington Road, Princeton University, Princeton, NJ 08544, USA
    Science 330:1344-8. 2010
    ..A powerful promoter of metabolic homeostasis at both the cellular and whole-animal level, autophagy prevents degenerative diseases. It does have a downside, however--cancer cells exploit it to survive in nutrient-poor tumors...
  26. pmc Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night
    Robin Mathew
    The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
    Curr Opin Genet Dev 21:113-9. 2011
    ..A better understanding of how autophagy modulates cell metabolism under various cellular stresses and the consequences of this on tumorigenesis will help develop better therapeutic strategies against cancer prevention and treatment...
  27. pmc Autophagy is required for glucose homeostasis and lung tumor maintenance
    Gizem Karsli-Uzunbas
    Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey
    Cancer Discov 4:914-27. 2014
    ..This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer...

Research Grants30

  1. CELLULAR AND MOLECULAR MECHANISMS OF GASTROINTESTINAL CANCERS
    Lopa Mishra; Fiscal Year: 2013
    ..Significantly, this program promises to yield new therapies targeted at these difficult-to-treat lethal cancers at the bench, and then to translate the results rapidly into clinical care, at the bedside. ..
  2. SPORE in GI Cancer
    Robert J Coffey; Fiscal Year: 2013
    ..Administrative Core B. Translational Pathology &Imaging Core C. Biostatistics &Bioinformatics Career Development Program Developmental Research Program ..
  3. SPORE IN LUNG CANCER
    Mark A Socinski; Fiscal Year: 2013
    ..abstract_text> ..
  4. Structure and Function of DNA Repair Enzymes
    Susan S Wallace; Fiscal Year: 2013
    ..In addition to bioinformatics for all projects, Core A will also perform kinetics analysis for Projects 2-4. Core C will provide the administrative underpinnings for the project. ..
  5. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  6. Host Defense Regulation and Viral Oncogenesis
    Glen N Barber; Fiscal Year: 2013
    ..PROJECT II, William Harrington, Jr., M.D.: Host Defense regulation by HTLV-1. PROJECT III, Enrique Mesri, Ph.D.: HHV8 (KSHV)-Mediated Regulation of Host Defense. ..
  7. Statistical Informatics for Cancer Research
    Xihong Lin; Fiscal Year: 2013
    ..The Program PIs, Professors Xihong Lin and Francesca Dominici, are renowned biostatisticians with strong track records of methodological and collaborative research and academic administration. ..
  8. Molecular Characterization of Autophagy in Salivary Gland Tumors
    David K Ann; Fiscal Year: 2013
    ..Furthermore, the new knowledge will have potential relevance to the role of autophagy in regulating other oncogenic Ras-induced cancers. ..
  9. Oklahoma Center of Biomedical Research Excellence (COBRE) in Structural Biology
    Ann H West; Fiscal Year: 2013
    ..Collectively, these specific aims are expected to increase the pace, competitiveness and success rate of structural biology research groups in Oklahoma as they seek major independent external grant support. ..
  10. M.D. Anderson Gynecologic SPORE for Uterine Cancers
    KAREN HSIEH LU; Fiscal Year: 2013
    ..Four Cores will support these projects. Core A (Administrative Core), Core B (Pathology Core), Core C Biomarkers Core, and Core D (Biostatistics and Bioinformatics Core). ..
  11. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  12. The ARF Tumor Suppressor
    Maureen E Murphy; Fiscal Year: 2013
    ..We believe that the requirement for ARF and autophagy may be an Achilles Heel for tumor cells. This research is aimed at understanding this pathway, and at finding ways to manipulate this pathway to combat cancer. ..
  13. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  14. Physiology of Class III PI 3-kinase Signaling 2
    Jonathan M Backer; Fiscal Year: 2013
    ..Given that hVps34 is one of the key kinases involved in autophagy, a better understanding of its regulation will lead to new insights into this critical cellular process. ..
  15. Mechanisms of GVHD
    Joseph H Antin; Fiscal Year: 2013
    ..Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective. ..
  16. Innate/Adaptive Immune Interactions in Gut Inflammation
    Sergio A Lira; Fiscal Year: 2013
    ..Overall the focus and interactive nature of the program (20 joint publications in 4 years, 3 additional NIH grants on related areas) provide a solid basis for a productive outcome. ..
  17. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  18. Identification of Metabolic Vulnerabilities of Ras-Driven Cancer Cells
    Eileen White; Fiscal Year: 2013
    ..Eileen White (Rutgers University) and Dr. Josh Rabinowitz (Princeton University) previously funded by a NIH Challenge Grant on cancer metabolism. ..
  19. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..