This article is original from Translational Medicine Network. Please indicate the source when reprinting
Author: Mia
Introduction: Autophagy , also known as macroautophagy, is an evolutionarily conserved lysosomal degradation catabolic process. Cells maintain internal cell homeostasis by recovering nutrients from damaged organelles and protein . Autophagy is the main reason for drug resistance caused by anti-cancer treatment. Scientists have made numerous efforts to understand and overcome autophagy-mediated therapeutic resistance, but none of these efforts have been successful in clinical applications.
On October 26, 2022, the team of Chen Xiang and Liu Hong of Central South University Xiangya Hospital, Houston Health Science Center, and Houston Health Science Center, and Huazhong University of Science and Technology Houston University of Science and Technology Guo Anyuan published a research paper entitled "Multi-omics characterization of autophagy-related molecular features for therapeutic targeting of autophagy" in the Nature Communications. The study used a one-sample gene set enrichment analysis (ssGSEA), which evaluated autophagy status in large cancer samples, and then conducted a comprehensive analysis to understand molecular changes in autophagy.
https://www.nature.com/articles/s41467-022-33946-x#Sec
Research Background
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autophagy, also known as macroautophagy, is an evolutionarily conserved lysosomal degradation catabolic process. Cells maintain intracellular homeostasis by retrieving nutrients from damaged organelles and proteins. Autophagy, as a crosstalk of multiple biological processes, can affect cancer by multilayer molecular changes from genomics to transcriptomics and proteomics . However, there is currently no comprehensive multiomic analysis of to elaborate on molecular alterations associated with cancer autophagy in .
Recent studies demonstrated the estimation of the robustness of autophagy through LC3-based detection, SQSTM1/p62-based detection, and direct observation of autophagy-related structures by electron microscopy . However, under both human physiological and pathological conditions, these methods are currently unfeasible. In addition, many studies have shown that autophagy is a key antibiotic resistance mechanism in anti-cancer treatment, and autophagy inhibition can improve drug sensitivity . Based on this promising evidence, dozens of clinical trials involving autophagy inhibitors are underway.
Study Overview
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researchers estimated tumor autophagy status in approximately 10,000 tumor samples of 33 cancer types in the Cancer Genome Map (TCGA).
To understand the common patterns of molecular changes associated with the autophagy process, the researchers divided these TCGA samples into high autophagy score groups, medium score groups, and low score groups. A total of 24 tumor types were tested in the high autophagy score group and the low autophagy score group, and five different molecular characteristics of these 24 cancer types were then tested, including 20,288 mRNAs, 218 proteins, 2435 miRNAs, 3785 mutations and 450 somatic copy number alterations (SCNAs). Among them, mRNA expression showed the largest number of variations; while somatic mutations showed the smallest variants, with only 51 mutations in the eight cancer types. The frequency of each molecular feature in different molecular profiles varies greatly between cancers .
To further understand the regulatory network in autophagy, in at least four cancers, researchers identified 36 autophagy-related miRNAs and constructed miRNA target regulatory networks. The researchers found that miRNA-targeted genes are enriched in multiple autophagy-related pathways, including PI3K-AKT and MAPK signaling pathways . In addition, 94 transcription factors (TFs) changed significantly in at least nine cancers, and this TF targeted 1759 significantly changed mRNAs. TF-targeted mRNA is enriched in 9 signaling pathways, including the autophagy-associated PI3K-AKT signaling pathway. The research results show that TF plays an important regulatory role in autophagy . In addition, SCNAs associated with autophagy can affect the sensitivity of anticancer drugs, including targeted therapy and immunotherapy for drug .
researchers also found that among the 20 cancer types, a total of 32 CAGs changed significantly, and that multiple cancer types were resistant or sensitive to drugs targeting these CAGs when autophagy was induced.Contrary to the traditional view that autophagy inhibition brings drug sensitivity, comprehensive analysis and in vitro/in vivo experiments highlight the opportunity to overcome autophagy-induced multidrug resistance using personalized molecular characterization analysis. Furthermore, further analysis showed that DDIT4 is a potential target that mediates autophagy induction to to sensitize tumor cells to etoposide .
Potential mechanism of drug responses of autophagy inducers sensitized by drugs
Research summary
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At present, most of the studies have focused on autophagy inhibition, and ignore the importance of autophagy induction. This has led to limited understanding of how the autophagic microenvironment affects molecular characteristics and cannot explain the unexpected adverse drug results in anti-cancer treatment. However, this study highlights the importance of monitoring tumor autophagy status in future clinical studies.
Reference materials:
https://www.nature.com/articles/s41467-022-33946-x#Sec2
Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment plans. If you need health guidance, please go to a regular hospital for treatment.
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