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Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer
Despite a critical role for MYC as an effector of oncogenic RAS, strategies to target MYC activity in RAS-driven cancers are lacking. In genetically engineered mouse models of lung and pancreatic cancer, oncogenic KRAS is insufficient to drive tumorigenesis, while addition of modest MYC overexpressi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398167/ https://www.ncbi.nlm.nih.gov/pubmed/32434218 http://dx.doi.org/10.1084/jem.20191805 |
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author | Bhattacharyya, Sohinee Oon, Chet Kothari, Aayush Horton, Wesley Link, Jason Sears, Rosalie C. Sherman, Mara H. |
author_facet | Bhattacharyya, Sohinee Oon, Chet Kothari, Aayush Horton, Wesley Link, Jason Sears, Rosalie C. Sherman, Mara H. |
author_sort | Bhattacharyya, Sohinee |
collection | PubMed |
description | Despite a critical role for MYC as an effector of oncogenic RAS, strategies to target MYC activity in RAS-driven cancers are lacking. In genetically engineered mouse models of lung and pancreatic cancer, oncogenic KRAS is insufficient to drive tumorigenesis, while addition of modest MYC overexpression drives robust tumor formation, suggesting that mechanisms beyond the RAS pathway play key roles in MYC regulation and RAS-driven tumorigenesis. Here we show that acidic fibroblast growth factor (FGF1) derived from cancer-associated fibroblasts (CAFs) cooperates with cancer cell–autonomous signals to increase MYC level, promoter occupancy, and activity. FGF1 is necessary and sufficient for paracrine regulation of MYC protein stability, signaling through AKT and GSK-3β to increase MYC half-life. Patient specimens reveal a strong correlation between stromal CAF content and MYC protein level in the neoplastic compartment, and identify CAFs as the specific source of FGF1 in the tumor microenvironment. Together, our findings demonstrate that MYC is coordinately regulated by cell-autonomous and microenvironmental signals, and establish CAF-derived FGF1 as a novel paracrine regulator of oncogenic transcription. |
format | Online Article Text |
id | pubmed-7398167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-73981672021-02-03 Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer Bhattacharyya, Sohinee Oon, Chet Kothari, Aayush Horton, Wesley Link, Jason Sears, Rosalie C. Sherman, Mara H. J Exp Med Brief Definitive Report Despite a critical role for MYC as an effector of oncogenic RAS, strategies to target MYC activity in RAS-driven cancers are lacking. In genetically engineered mouse models of lung and pancreatic cancer, oncogenic KRAS is insufficient to drive tumorigenesis, while addition of modest MYC overexpression drives robust tumor formation, suggesting that mechanisms beyond the RAS pathway play key roles in MYC regulation and RAS-driven tumorigenesis. Here we show that acidic fibroblast growth factor (FGF1) derived from cancer-associated fibroblasts (CAFs) cooperates with cancer cell–autonomous signals to increase MYC level, promoter occupancy, and activity. FGF1 is necessary and sufficient for paracrine regulation of MYC protein stability, signaling through AKT and GSK-3β to increase MYC half-life. Patient specimens reveal a strong correlation between stromal CAF content and MYC protein level in the neoplastic compartment, and identify CAFs as the specific source of FGF1 in the tumor microenvironment. Together, our findings demonstrate that MYC is coordinately regulated by cell-autonomous and microenvironmental signals, and establish CAF-derived FGF1 as a novel paracrine regulator of oncogenic transcription. Rockefeller University Press 2020-05-20 /pmc/articles/PMC7398167/ /pubmed/32434218 http://dx.doi.org/10.1084/jem.20191805 Text en © 2020 Bhattacharyya et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Brief Definitive Report Bhattacharyya, Sohinee Oon, Chet Kothari, Aayush Horton, Wesley Link, Jason Sears, Rosalie C. Sherman, Mara H. Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer |
title | Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer |
title_full | Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer |
title_fullStr | Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer |
title_full_unstemmed | Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer |
title_short | Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer |
title_sort | acidic fibroblast growth factor underlies microenvironmental regulation of myc in pancreatic cancer |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398167/ https://www.ncbi.nlm.nih.gov/pubmed/32434218 http://dx.doi.org/10.1084/jem.20191805 |
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