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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...

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Autores principales: Bhattacharyya, Sohinee, Oon, Chet, Kothari, Aayush, Horton, Wesley, Link, Jason, Sears, Rosalie C., Sherman, Mara H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
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.
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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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