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An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance

Xu, S and Ware, KE and Ding, Y and Kim, SY and Sheth, MU and Rao, S and Chan, W and Armstrong, AJ and Eward, WC and Jolly, MK and Somarelli, JA (2019) An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance. In: Journal of Clinical Medicine, 8 (2).

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Official URL: https://doi.org/10.3390/jcm8020205


The evolution of therapeutic resistance is a major cause of death for cancer patients. The development of therapy resistance is shaped by the ecological dynamics within the tumor microenvironment and the selective pressure of the host immune system. These selective forces often lead to evolutionary convergence on pathways or hallmarks that drive progression. Thus, a deeper understanding of the evolutionary convergences that occur could reveal vulnerabilities to treat therapy-resistant cancer. To this end, we combined phylogenetic clustering, systems biology analyses, and molecular experimentation to identify convergences in gene expression data onto common signaling pathways. We applied these methods to derive new insights about the networks at play during transforming growth factor-β (TGF-β)-mediated epithelial–mesenchymal transition in lung cancer. Phylogenetic analyses of gene expression data from TGF-β-treated cells revealed convergence of cells toward amine metabolic pathways and autophagy during TGF-β treatment. Knockdown of the autophagy regulatory, ATG16L1, re-sensitized lung cancer cells to cancer therapies following TGF-β-induced resistance, implicating autophagy as a TGF-β-mediated chemoresistance mechanism. In addition, high ATG16L expression was found to be a poor prognostic marker in multiple cancer types. These analyses reveal the usefulness of combining evolutionary and systems biology methods with experimental validation to illuminate new therapeutic vulnerabilities for cancer.

Item Type: Journal Article
Publication: Journal of Clinical Medicine
Publisher: MDPI
Additional Information: The copyright for this article belongs to the Authors.
Keywords: transforming growth factor beta, ammonia formation; apoptosis; Article; ATG16L1 gene; autophagy; cancer patient; cause of death; cell migration; clinical outcome; epithelial mesenchymal transition; gene; gene cluster; gene expression; high throughput screening; human; immune system; immunohistochemistry; integrative medicine; lung cancer; maximum likelihood method; metabolism; phenotype; phylogeny; plasticity; protein expression; quality control; real time polymerase chain reaction; reverse transcription polymerase chain reaction; RNA extraction; signal transduction; systems biology; tumor growth; tumor microenvironment; upregulation; Western blotting
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 25 Oct 2022 10:29
Last Modified: 25 Oct 2022 10:29
URI: https://eprints.iisc.ac.in/id/eprint/77563

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