title: Autophagy is required for glucose homeostasis and lung tumor maintenance.
abstract: Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non-small cell lung cancer (NSCLC) initiation by activation of oncogenic Kras(G12D) and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer.
  
  
  CONCLUSIONS
  We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers.
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.
authors.forename: Gizem
authors.initials: G
authors.lastname: Karsli-Uzunbas
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.
authors.forename: Jessie Yanxiang
authors.initials: JY
authors.lastname: Guo
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Sandy
authors.initials: S
authors.lastname: Price
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey.
authors.forename: Xin
authors.initials: X
authors.lastname: Teng
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Saurabh V
authors.initials: SV
authors.lastname: Laddha
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.
authors.forename: Sinan
authors.initials: S
authors.lastname: Khor
authors.affiliation: Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nada Y
authors.initials: NY
authors.lastname: Kalaany
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, MIT, Cambridge, Massachusetts. Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Deparment of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.
authors.forename: Chang S
authors.initials: CS
authors.lastname: Chan
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Chemistry, Princeton University, Princeton, New Jersey.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey. epwhite@cinj.rutgers.edu.
authors.forename: Eileen
authors.initials: E
authors.lastname: White
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071193:Autophagy-Related Protein 7; D002100:Cachexia / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000071193:Autophagy-Related Protein 7; D005947:Glucose