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Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types
Signal transduction pathways are important in physiology and pathophysiology. Targeted drugs aim at modifying pathogenic pathway activity, e.g., in cancer. Optimal treatment choice requires assays to measure pathway activity in individual patient tissue or cell samples. We developed a method enablin...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367506/ https://www.ncbi.nlm.nih.gov/pubmed/30733525 http://dx.doi.org/10.1038/s41598-018-38179-x |
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author | Stolpe, Anja van de Holtzer, Laurent van Ooijen, Henk de Inda, Marcia Alves Verhaegh, Wim |
author_facet | Stolpe, Anja van de Holtzer, Laurent van Ooijen, Henk de Inda, Marcia Alves Verhaegh, Wim |
author_sort | Stolpe, Anja van de |
collection | PubMed |
description | Signal transduction pathways are important in physiology and pathophysiology. Targeted drugs aim at modifying pathogenic pathway activity, e.g., in cancer. Optimal treatment choice requires assays to measure pathway activity in individual patient tissue or cell samples. We developed a method enabling quantitative measurement of functional pathway activity based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the pathway-associated transcription factor. Oestrogen receptor, Wnt, and PI3K-FOXO pathway assays have been described previously. Here, we report model development for androgen receptor, Hedgehog, TGFβ, and NFκB pathway assays, biological validation on multiple cell types, and analysis of data from published clinical studies (multiple sclerosis, amyotrophic lateral sclerosis, contact dermatitis, Ewing sarcoma, lymphoma, medulloblastoma, ependymoma, skin and prostate cancer). Multiple pathway analysis of clinical prostate cancer (PCa) studies showed increased AR activity in hyperplasia and primary PCa but variable AR activity in castrate resistant (CR) PCa, loss of TGFβ activity in PCa, increased Wnt activity in TMPRSS2:ERG fusion protein-positive PCa, active PI3K pathway in advanced PCa, and active PI3K and NFκB as potential hormonal resistance pathways. Potential value for future clinical practice includes disease subtyping and prediction and targeted therapy response prediction and monitoring. |
format | Online Article Text |
id | pubmed-6367506 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63675062019-02-11 Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types Stolpe, Anja van de Holtzer, Laurent van Ooijen, Henk de Inda, Marcia Alves Verhaegh, Wim Sci Rep Article Signal transduction pathways are important in physiology and pathophysiology. Targeted drugs aim at modifying pathogenic pathway activity, e.g., in cancer. Optimal treatment choice requires assays to measure pathway activity in individual patient tissue or cell samples. We developed a method enabling quantitative measurement of functional pathway activity based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the pathway-associated transcription factor. Oestrogen receptor, Wnt, and PI3K-FOXO pathway assays have been described previously. Here, we report model development for androgen receptor, Hedgehog, TGFβ, and NFκB pathway assays, biological validation on multiple cell types, and analysis of data from published clinical studies (multiple sclerosis, amyotrophic lateral sclerosis, contact dermatitis, Ewing sarcoma, lymphoma, medulloblastoma, ependymoma, skin and prostate cancer). Multiple pathway analysis of clinical prostate cancer (PCa) studies showed increased AR activity in hyperplasia and primary PCa but variable AR activity in castrate resistant (CR) PCa, loss of TGFβ activity in PCa, increased Wnt activity in TMPRSS2:ERG fusion protein-positive PCa, active PI3K pathway in advanced PCa, and active PI3K and NFκB as potential hormonal resistance pathways. Potential value for future clinical practice includes disease subtyping and prediction and targeted therapy response prediction and monitoring. Nature Publishing Group UK 2019-02-07 /pmc/articles/PMC6367506/ /pubmed/30733525 http://dx.doi.org/10.1038/s41598-018-38179-x Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Stolpe, Anja van de Holtzer, Laurent van Ooijen, Henk de Inda, Marcia Alves Verhaegh, Wim Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types |
title | Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types |
title_full | Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types |
title_fullStr | Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types |
title_full_unstemmed | Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types |
title_short | Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types |
title_sort | enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367506/ https://www.ncbi.nlm.nih.gov/pubmed/30733525 http://dx.doi.org/10.1038/s41598-018-38179-x |
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