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Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer

Jindal, R and Nanda, A and Pillai, M and Ware, KE and Singh, D and Sehgal, M and Armstrong, AJ and Somarelli, JA and Jolly, MK (2023) Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer. In: Computational and Structural Biotechnology Journal, 21 . 1498 – 1509.

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Official URL: https://10.1016/j.csbj.2023.01.031


Advanced prostate cancer patients initially respond to hormone therapy, be it in the form of androgen deprivation therapy or second-generation hormone therapies, such as abiraterone acetate or enzalutamide. However, most men with prostate cancer eventually develop hormone therapy resistance. This resistance can arise through multiple mechanisms, such as through genetic mutations, epigenetic mechanisms, or through non-genetic pathways, such as lineage plasticity along epithelial-mesenchymal or neuroendocrine-like axes. These mechanisms of hormone therapy resistance often co-exist within a single patient's tumor and can overlap within a single cell. There exists a growing need to better understand how phenotypic heterogeneity and plasticity results from emergent dynamics of the regulatory networks governing androgen independence. Here, we investigated the dynamics of a regulatory network connecting the drivers of androgen receptor (AR) splice variant-mediated androgen independence and those of epithelial-mesenchymal transition. Model simulations for this network revealed four possible phenotypes: epithelial-sensitive (ES), epithelial-resistant (ER), mesenchymal-resistant (MR) and mesenchymal-sensitive (MS), with the latter phenotype occurring rarely. We observed that well-coordinated “teams” of regulators working antagonistically within the network enable these phenotypes. These model predictions are supported by multiple transcriptomic datasets both at single-cell and bulk levels, including in vitro EMT induction models and clinical samples. Further, our simulations reveal spontaneous stochastic switching between the ES and MR states. Addition of the immune checkpoint molecule, PD-L1, to the network was able to capture the interactions between AR, PD-L1, and the mesenchymal marker SNAIL, which was also confirmed through quantitative experiments. This systems-level understanding of the driver of androgen independence and EMT could aid in understanding non-genetic transitions and progression of such cancers and help in identifying novel therapeutic strategies or targets. © 2023 The Authors

Item Type: Journal Article
Publication: Computational and Structural Biotechnology Journal
Publisher: Elsevier B.V.
Additional Information: The copyright of this article belongs to the Authors.
Keywords: Diseases; Molluscs; Patient treatment; Stochastic systems; Urology; androgen; androgen receptor; enzalutamide; immune checkpoint protein; microRNA; programmed death 1 ligand 1; transcription factor; transcription factor Snail; Androgen independence; Epithelial-mesenchymal transition; Genetic heterogeneities; Hormone therapy; Multistability; Non-genetic heterogeneity; PD-l1; Phenotypic plasticity; Regulatory network; Snail; advanced cancer; alternative RNA splicing; animal cell; Article; cancer hormone therapy; cancer resistance; castration resistant prostate cancer; controlled study; dimensionality reduction; epithelial mesenchymal transition; gene regulatory network; human; human tissue; immune evasion; immunoblotting; in vitro study; male; mathematical model; mouse; nonhuman; phenotype; phenotypic plasticity; prediction; prostate cancer; transcriptomics; Dynamics
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 09 Mar 2023 07:11
Last Modified: 09 Mar 2023 07:11
URI: https://eprints.iisc.ac.in/id/eprint/80945

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