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

Publication ,  Journal Article
Jindal, R; Nanda, A; Pillai, M; Ware, KE; Singh, D; Sehgal, M; Armstrong, AJ; Somarelli, JA; Jolly, MK
Published in: Comput Struct Biotechnol J
2023

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.

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Published In

Comput Struct Biotechnol J

DOI

ISSN

2001-0370

Publication Date

2023

Volume

21

Start / End Page

1498 / 1509

Location

Netherlands

Related Subject Headings

  • 4601 Applied computing
  • 3101 Biochemistry and cell biology
  • 0802 Computation Theory and Mathematics
  • 0103 Numerical and Computational Mathematics
 

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Jindal, R., Nanda, A., Pillai, M., Ware, K. E., Singh, D., Sehgal, M., … Jolly, M. K. (2023). Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer. Comput Struct Biotechnol J, 21, 1498–1509. https://doi.org/10.1016/j.csbj.2023.01.031
Jindal, Rashi, Abheepsa Nanda, Maalavika Pillai, Kathryn E. Ware, Divyoj Singh, Manas Sehgal, Andrew J. Armstrong, Jason A. Somarelli, and Mohit Kumar Jolly. “Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer.Comput Struct Biotechnol J 21 (2023): 1498–1509. https://doi.org/10.1016/j.csbj.2023.01.031.
Jindal R, Nanda A, Pillai M, Ware KE, Singh D, Sehgal M, et al. Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer. Comput Struct Biotechnol J. 2023;21:1498–509.
Jindal, Rashi, et al. “Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer.Comput Struct Biotechnol J, vol. 21, 2023, pp. 1498–509. Pubmed, doi:10.1016/j.csbj.2023.01.031.
Jindal R, Nanda A, Pillai M, Ware KE, Singh D, Sehgal M, Armstrong AJ, Somarelli JA, Jolly MK. Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer. Comput Struct Biotechnol J. 2023;21:1498–1509.

Published In

Comput Struct Biotechnol J

DOI

ISSN

2001-0370

Publication Date

2023

Volume

21

Start / End Page

1498 / 1509

Location

Netherlands

Related Subject Headings

  • 4601 Applied computing
  • 3101 Biochemistry and cell biology
  • 0802 Computation Theory and Mathematics
  • 0103 Numerical and Computational Mathematics