Science and Research

Robustness of the Autophagy Pathway to Somatic Copy Number Losses

Autophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and open a therapeutic window. While mutations of autophagy genes (ATGs) are notably rare in cancer, haploinsufficiency network analyses across many cancers have shown that the autophagy pathway is frequently hit by somatic copy number losses of ATGs such as MAP1LC3B/ATG8F (LC3), BECN1/ATG6 (Beclin-1), and ATG10. Here, we used CRISPR/Cas9 technology to delete increasing numbers of copies of one or more of these ATGs in non-small cell lung cancer cells and examined the effects on sensitivity to compounds targeting aerobic glycolysis, a hallmark of cancer metabolism. Whereas the complete knockout of one ATG blocked autophagy and led to profound metabolic vulnerability, this was not the case for combinations of different nonhomozygous deletions. In cancer patients, the effect of ATG copy number loss was blunted at the protein level and did not lead to the accumulation of p62 as a sign of reduced autophagic flux. Thus, the autophagy pathway is shown to be markedly robust and resilient, even with the concomitant copy number loss of key autophagy genes.

  • Polo, P.
  • Gremke, N.
  • Stiewe, T.
  • Wanzel, M.

Keywords

  • Autophagy/genetics
  • Beclin-1/genetics
  • *Carcinoma, Non-Small-Cell Lung/genetics
  • DNA Copy Number Variations/genetics
  • Humans
  • *Lung Neoplasms/genetics
  • aerobic glycolysis
  • autophagy
  • cancer metabolism
  • copy number loss
  • haploinsufficiency
  • metabolic cancer therapy
  • somatic copy number alterations (SCNAs)
Publication details
DOI: 10.3390/cells11111762
Journal: Cells
Number: 11
Work Type: Original
Location: UGMLC
Disease Area: LC
Partner / Member: JLU, UMR
Access-Number: 35681458

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