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Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer
Survival rates of patients with metastatic castration-resistant prostate cancer (mCRPC) are low due to lack of response or acquired resistance to available therapies, such as abiraterone (Abi). A better understanding of the underlying molecular mechanisms is needed to identify effective targets to o...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10102853/ https://www.ncbi.nlm.nih.gov/pubmed/36779846 http://dx.doi.org/10.1158/0008-5472.CAN-22-1910 |
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author | Blatti, Charles de la Fuente, Jesús Gao, Huanyao Marín-Goñi, Irene Chen, Zikun Zhao, Sihai D. Tan, Winston Weinshilboum, Richard Kalari, Krishna R. Wang, Liewei Hernaez, Mikel |
author_facet | Blatti, Charles de la Fuente, Jesús Gao, Huanyao Marín-Goñi, Irene Chen, Zikun Zhao, Sihai D. Tan, Winston Weinshilboum, Richard Kalari, Krishna R. Wang, Liewei Hernaez, Mikel |
author_sort | Blatti, Charles |
collection | PubMed |
description | Survival rates of patients with metastatic castration-resistant prostate cancer (mCRPC) are low due to lack of response or acquired resistance to available therapies, such as abiraterone (Abi). A better understanding of the underlying molecular mechanisms is needed to identify effective targets to overcome resistance. Given the complexity of the transcriptional dynamics in cells, differential gene expression analysis of bulk transcriptomics data cannot provide sufficient detailed insights into resistance mechanisms. Incorporating network structures could overcome this limitation to provide a global and functional perspective of Abi resistance in mCRPC. Here, we developed TraRe, a computational method using sparse Bayesian models to examine phenotypically driven transcriptional mechanistic differences at three distinct levels: transcriptional networks, specific regulons, and individual transcription factors (TF). TraRe was applied to transcriptomic data from 46 patients with mCRPC with Abi-response clinical data and uncovered abrogated immune response transcriptional modules that showed strong differential regulation in Abi-responsive compared with Abi-resistant patients. These modules were replicated in an independent mCRPC study. Furthermore, key rewiring predictions and their associated TFs were experimentally validated in two prostate cancer cell lines with different Abi-resistance features. Among them, ELK3, MXD1, and MYB played a differential role in cell survival in Abi-sensitive and Abi-resistant cells. Moreover, ELK3 regulated cell migration capacity, which could have a direct impact on mCRPC. Collectively, these findings shed light on the underlying transcriptional mechanisms driving Abi response, demonstrating that TraRe is a promising tool for generating novel hypotheses based on identified transcriptional network disruptions. SIGNIFICANCE: The computational method TraRe built on Bayesian machine learning models for investigating transcriptional network structures shows that disruption of ELK3, MXD1, and MYB signaling cascades impacts abiraterone resistance in prostate cancer. |
format | Online Article Text |
id | pubmed-10102853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-101028532023-04-15 Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer Blatti, Charles de la Fuente, Jesús Gao, Huanyao Marín-Goñi, Irene Chen, Zikun Zhao, Sihai D. Tan, Winston Weinshilboum, Richard Kalari, Krishna R. Wang, Liewei Hernaez, Mikel Cancer Res Convergence and Technologies Survival rates of patients with metastatic castration-resistant prostate cancer (mCRPC) are low due to lack of response or acquired resistance to available therapies, such as abiraterone (Abi). A better understanding of the underlying molecular mechanisms is needed to identify effective targets to overcome resistance. Given the complexity of the transcriptional dynamics in cells, differential gene expression analysis of bulk transcriptomics data cannot provide sufficient detailed insights into resistance mechanisms. Incorporating network structures could overcome this limitation to provide a global and functional perspective of Abi resistance in mCRPC. Here, we developed TraRe, a computational method using sparse Bayesian models to examine phenotypically driven transcriptional mechanistic differences at three distinct levels: transcriptional networks, specific regulons, and individual transcription factors (TF). TraRe was applied to transcriptomic data from 46 patients with mCRPC with Abi-response clinical data and uncovered abrogated immune response transcriptional modules that showed strong differential regulation in Abi-responsive compared with Abi-resistant patients. These modules were replicated in an independent mCRPC study. Furthermore, key rewiring predictions and their associated TFs were experimentally validated in two prostate cancer cell lines with different Abi-resistance features. Among them, ELK3, MXD1, and MYB played a differential role in cell survival in Abi-sensitive and Abi-resistant cells. Moreover, ELK3 regulated cell migration capacity, which could have a direct impact on mCRPC. Collectively, these findings shed light on the underlying transcriptional mechanisms driving Abi response, demonstrating that TraRe is a promising tool for generating novel hypotheses based on identified transcriptional network disruptions. SIGNIFICANCE: The computational method TraRe built on Bayesian machine learning models for investigating transcriptional network structures shows that disruption of ELK3, MXD1, and MYB signaling cascades impacts abiraterone resistance in prostate cancer. American Association for Cancer Research 2023-04-14 2023-02-13 /pmc/articles/PMC10102853/ /pubmed/36779846 http://dx.doi.org/10.1158/0008-5472.CAN-22-1910 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Convergence and Technologies Blatti, Charles de la Fuente, Jesús Gao, Huanyao Marín-Goñi, Irene Chen, Zikun Zhao, Sihai D. Tan, Winston Weinshilboum, Richard Kalari, Krishna R. Wang, Liewei Hernaez, Mikel Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer |
title | Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer |
title_full | Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer |
title_fullStr | Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer |
title_full_unstemmed | Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer |
title_short | Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer |
title_sort | bayesian machine learning enables identification of transcriptional network disruptions associated with drug-resistant prostate cancer |
topic | Convergence and Technologies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10102853/ https://www.ncbi.nlm.nih.gov/pubmed/36779846 http://dx.doi.org/10.1158/0008-5472.CAN-22-1910 |
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