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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Autophagy is a cellular process implicated in cancer therapy resistance.
• Previous attempts to target autophagy for overcoming resistance have yielded limited clinical success.

Purpose of the Study:

• To develop an autophagy signature for assessing tumor autophagy status.
• To investigate the relationship between tumor autophagy and molecular features.
• To analyze how autophagy influences drug response in various cancer types.

Main Methods:

• Established a novel autophagy signature to quantify tumor autophagy.
• Classified ~10,000 tumor samples from The Cancer Genome Atlas (TCGA) into high and low autophagy groups.
• Characterized multi-dimensional molecular features and analyzed drug sensitivity based on autophagy status.

Main Results:

• Contrary to the established view, autophagy induction can sensitize cancer cells to anti-cancer drugs.
• Experimental validation confirmed that autophagy inducers can sensitize tumor cells to etoposide.
• Downregulation of DDIT4 expression was identified as a mechanism for etoposide sensitization by autophagy inducers.

Conclusions:

• This study provides a comprehensive molecular landscape of tumor autophagy.
• Autophagy's dual role in therapy resistance and sensitization presents new therapeutic opportunities.
• Multi-omics analysis can guide the use of autophagy-modulating strategies for enhanced drug sensitivity.