https://archiv.ub.uni-marburg.de/es/2023/0017/cover.png 2023-03-06 Medizin metabolic cancer ther 2023-03-06 https://doi.org/10.3390/cells11111762 haploinsufficiency 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. 2023 Polo, Pierfrancesco Polo Pierfrancesco Gremke, Niklas Gremke Niklas Stiewe, Thorsten Stiewe Thorsten Wanzel, Michael Wanzel Michael article opus:11251 cancer metabolism somatic copy number alterations (SCNAs) //archiv.ub.uni-marburg.de/es/2022/0096/cover.png In der Sammlung befinden sich alle seit 2022 vom Open-Access-Publikationsfonds der UB Marburg geförderten wissenschaftlichen Publikationen als Zweitveröffentlichung. Neben Eigenmitteln der Philipps-Universität Marburg beinhaltet der Fonds auch Zuschüsse der Deutschen Forschungsgemeinschaft. urn:nbn:de:hebis:04-es2022-00967 Publikationen im Open Access gefördert durch die UB Publikationsserver der Universitätsbibliothek Marburg Universitätsbibliothek Marburg article Erstveröffentlichung: Polo, P.; Gremke, N.; Stiewe, T.;Wanzel, M. Robustness of the Autophagy Pathway to Somatic Copy Number Losses. Cells 2022, 11, 1762. https://doi.org/10.3390/cells11111762 Medical sciences Medicine Medizin urn:nbn:de:hebis:04-es2023-00175 English Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. copy number loss autophagy aerobic glycolysis Medizin 15 application/pdf Philipps-Universität Marburg Robustness of the Autophagy Pathway to Somatic Copy Number Losses