Multi-omics characterization of autophagy-related molecular features for therapeutic targeting of autophagy

Mei Luo, Lin Ye, Ruimin Chang, Youqiong Ye, Zhao Zhang, Chunjie Liu, Shengli Li, Ying Jing, Hang Ruan, Guanxiong Zhang, Yi He, Yaoming Liu, Yu Xue, Xiang Chen (), An-Yuan Guo (), Hong Liu () and Leng Han ()
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Mei Luo: Central South University
Lin Ye: Central South University
Ruimin Chang: Central South University
Youqiong Ye: McGovern Medical School at The University of Texas Health Science Center at Houston
Zhao Zhang: McGovern Medical School at The University of Texas Health Science Center at Houston
Chunjie Liu: Huazhong University of Science and Technology
Shengli Li: McGovern Medical School at The University of Texas Health Science Center at Houston
Ying Jing: McGovern Medical School at The University of Texas Health Science Center at Houston
Hang Ruan: McGovern Medical School at The University of Texas Health Science Center at Houston
Guanxiong Zhang: Central South University
Yi He: Central South University
Yaoming Liu: McGovern Medical School at The University of Texas Health Science Center at Houston
Yu Xue: Huazhong University of Science and Technology
Xiang Chen: Central South University
An-Yuan Guo: Huazhong University of Science and Technology
Hong Liu: Central South University
Leng Han: McGovern Medical School at The University of Texas Health Science Center at Houston

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Autophagy is a major contributor to anti-cancer therapy resistance. Many efforts have been made to understand and overcome autophagy-mediated therapy resistance, but these efforts have been unsuccessful in clinical applications. In this study, we establish an autophagy signature to estimate tumor autophagy status. We then classify approximately 10,000 tumor samples across 33 cancer types from The Cancer Genome Atlas into autophagy score-high and autophagy score-low groups. We characterize the associations between multi-dimensional molecular features and tumor autophagy, and further analyse the effects of autophagy status on drug response. In contrast to the conventional view that the induction of autophagy serves as a key resistance mechanism during cancer therapy, our analysis reveals that autophagy induction may also sensitize cancer cells to anti-cancer drugs. We further experimentally validate this phenomenon for several anti-cancer drugs in vitro and in vivo, and reveal that autophagy inducers potentially sensitizes tumor cells to etoposide through downregulating the expression level of DDIT4. Our study provides a comprehensive landscape of molecular alterations associated with tumor autophagy and highlights an opportunity to leverage multi-omics analysis to utilize multiple drug sensitivity induced by autophagy.

Date: 2022
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DOI: 10.1038/s41467-022-33946-x

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