Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis

Abstract

Macroautophagy (autophagy hereafter) degrades and recycles proteins and organelles to support metabolism and survival in starvation. Oncogenic Ras up-regulates autophagy, and Ras-transformed cell lines require autophagy for mitochondrial function, stress survival, and engrafted tumor growth. Here, the essential autophagy gene autophagy-related-7 (atg7 ) was deleted concurrently with K-ras G12D activation in mouse models for non-smallcell lung cancer (NSCLC). atg7-deficient tumors accumulated dysfunctional mitochondria and prematurely induced p53 and proliferative arrest, which reduced tumor burden that was partly relieved by p53 deletion. atg7 loss altered tumor fate from adenomas and carcinomas to oncocytomas-rare, predominantly benign tumors characterized by the accumulation of defective mitochondria. Surprisingly, lipid accumulation occurred in atg7-deficient tumors only when p53 was deleted. atg7-and p53-deficient tumor-derived cell lines (TDCLs) had compromised starvation survival and formed lipidic cysts instead of tumors, suggesting defective utilization of lipid stores. atg7 deficiency reduced fatty acid oxidation (FAO) and increased sensitivity to FAO inhibition, indicating that with p53 loss, Ras-driven tumors require autophagy for mitochondrial function and lipid catabolism. Thus, autophagy is required for carcinoma fate, and autophagy defects may be a molecular basis for the occurrence of oncocytomas. Moreover, cancers require autophagy for distinct roles in metabolism that are oncogene-and tumor suppressor gene-specific.

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis

“…26 In a separate study, it was also demonstrated that the loss of Atg5 or Atg7 could also prevent the development of high-grade pancreatic neoplastic legions induced by K-ras, and the pancreatic tumor growth could be restored if the expression of p53 was also abolished. 27 These recent findings together with ours indicate that autophagy is required for tumor progression for at least three different tumor types and that the deletion of p53 can partially restore tumorigenesis when autophagy is impaired.…”

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

“…26 The core autophagy machinery may be protected from alteration in some human cancers, an idea supported by recent studies in murine models of lung cancer that find autophagy to be essential for tumor progression. 27,28 Importantly, we found that clustering abundance profiles of AA genes stratified patient OS in 3 of 9 cancer types and grouped patients with similar pathophysiology together, linking the differential expression of autophagy regulators and interactors to clinical features known to influence patient outcome. This suggests that clinically relevant differential pathway activities exist between …”

“…72 Autophagy has been shown to support tumorigenesis in lung cancer, particularly in KRAS-driven lung cancer cell lines and animal models that may be addicted to high levels of autophagy, 73,74 and autophagy inactivation in KRasdriven mouse models of lung cancer impairs cell growth, proliferation, and tumor progression. 27,28 We stratified gene expression of all 211 AA genes in both LUAD and LUSC by known recurrent somatic disease-specific alterations, including EGFR and KRAS alterations, and did not find differences in core gene expression between altered and wild-type patients; however, LUSC patients with EGFR amplification had increased mRNA levels of NFE2L2 (median FC > 2; Table S5). Both overactive and impaired autophagy are hypothesized to support oncogenic NFE2L2 activity in cancer, 75 through increased degradation of the NFE2L2 sequestering protein KEAP1 51 or through reduced degradation of KEAP1 binding protein SQSTM1/p62, 76 respectively.…”

“…38,39 BNIP3's contribution to tumorigenesis has yet to be linked to its role in mitophagy; however, the fact that increased levels of BNIP3 are associated with more aggressive disease suggests that a function in tumor cell survival via autophagy or mitophagy is a more likely mechanistic scenario than a role in cell death, in contexts of BNIP3 overexpression. Autophagy has documented roles in KRAS-driven lung 27,28 and pancreatic 40,41 cancer progression, and overactive RAS has been shown to upregulate BNIP3. 42 Further investigation of autophagy status in RAS-driven tumors with BNIP3 overexpression may reveal a mechanistic link between BNIP3 and tumor cell survival.…”

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

“…It has been suggested to hold a tumour suppressive function during early tumourigenesis, [20][21][22][23][24][25][26][27] whereas it can also sustain cancer progression. [28][29][30][31][32][33][34][35][36] Increased levels of basal autophagy have been found in a variety of cancer tissues including colorectal cancer (CRC), where autophagy supports tumour growth and confers tumour aggressiveness. 31 Autophagy is inhibited by oncogenic tyrosine kinases (OncTKs) and receptor tyrosine kinases (RTKs) via activation of the PI3K/AKT/mTORC1 and RAS/MAPK signalling.…”