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

Shengnan Xu, Kathryn E Ware, Yuantong Ding, So Young Kim, Maya Sheth, Sneha Rao, Wesley Chan, Andrew J Armstrong, William C Eward, Mohit K Jolly, Jason A Somarelli
doi: https://doi.org/10.1101/365833
Shengnan Xu
Duke University;
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Kathryn E Ware
Duke University;
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Yuantong Ding
Duke University;
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So Young Kim
Duke University;
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Maya Sheth
Duke University;
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Sneha Rao
Duke University;
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Wesley Chan
Duke University;
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Andrew J Armstrong
Duke University;
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William C Eward
Duke University;
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Mohit K Jolly
Rice University
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  • For correspondence: mkjolly.15@gmail.com
Jason A Somarelli
Duke University;
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Abstract

The evolution of therapeutic resistance is a major cause of death for patients with solid tumors. The development of therapy resistance is shaped by the ecological dynamics within the tumor microenvironment and the selective pressure induced by the host immune system. These ecological and selective forces often lead to evolutionary convergence on one or more pathways or hallmarks that drive progression. These hallmarks are, in turn, intimately linked to each other through gene expression networks. Thus, a deeper understanding of the evolutionary convergences that occur at the gene expression level could reveal vulnerabilities that could be targeted to treat therapy-resistant cancer. To this end, we used a combination of phylogenetic clustering, systems biology analyses, and wet-bench 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 TGF-β-mediated epithelial-mesenchymal transition in a lung cancer model system. Phylogenetics analyses of gene expression data from TGF-β treated cells revealed evolutionary convergence of cells toward amine-metabolic pathways and autophagy during TGF-β treatment. Using high-throughput drug screens, we found that 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. Analysis of publicly-available clinical data sets validated the adverse prognostic importance of ATG16L expression in multiple cancer types including kidney, lung, and colon cancer patients. These analyses reveal the usefulness of combining evolutionary and systems biology methods with experimental validation to illuminate new therapeutic vulnerabilities.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 10, 2018.
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An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance
Shengnan Xu, Kathryn E Ware, Yuantong Ding, So Young Kim, Maya Sheth, Sneha Rao, Wesley Chan, Andrew J Armstrong, William C Eward, Mohit K Jolly, Jason A Somarelli
bioRxiv 365833; doi: https://doi.org/10.1101/365833
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An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance
Shengnan Xu, Kathryn E Ware, Yuantong Ding, So Young Kim, Maya Sheth, Sneha Rao, Wesley Chan, Andrew J Armstrong, William C Eward, Mohit K Jolly, Jason A Somarelli
bioRxiv 365833; doi: https://doi.org/10.1101/365833

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