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PYCR1-dependent proline synthesis in cancer-associated fibroblasts is required for the deposition of pro-tumorigenic extracellular matrix

Authors :
Henry Daebritz
Massimiliano Mazzone
Ann Hedley
Saverio Tardito
Claudia Boldrini
Lisa J. Neilson
Juan Ramon Hernandez-Fernaud
Emily J. Kay
Kristina Kirschner
Morag Park
Grigorios Koulouras
Michele Zagnoni
Enio Gjerga
Carla Riero Domingo
Grace McGregor
Sergio Lilla
David Sumpton
Jurre J. Kamphorst
Sara Zanivan
Radia M. Johnson
Craig Jamieson
Dimitris Athineos
Sandeep Dhayade
Karla Paterson
Crispin J. Miller
Fabricio Loayza-Puch
Ekaterina Stepanova
Julio Saez-Rodriguez
Karen Blyth
Publication Year :
2020
Publisher :
Cold Spring Harbor Laboratory, 2020.

Abstract

TElevated production of collagen-rich extracellular matrix (ECM) is a hallmark of cancer associated fibroblasts (CAFs) and a central driver of cancer aggressiveness. How to target ECM production to oppose cancer is yet unclear, since targeting CAFs has been shown to restrain but also promote cancer progression. Metabolic rewiring is a hallmark of CAFs. Here we find that proline, which is a highly abundant amino acid in collagen proteins, is newly synthesised from glutamine to make tumour collagen in breast cancer xenografts, and that its production is elevated in breast cancer CAFs. PYCR1 is the rate-limiting enzyme for proline synthesis and is highly expressed in the tumour stroma of breast cancer patients and in CAFs. Reducing PYCR1 levels in CAFs is sufficient to reduce tumour collagen production, tumour growth and metastatic spread in vivo and cancer cell proliferation in vitro. PYCR1 and COL1A1 are overexpressed in patients with invasive ductal carcinoma with poor prognosis. Both collagen and glutamine-derived proline synthesis in CAFs are enhanced by increased pyruvate dehydrogenase-derived acetyl-CoA levels, via gene expression regulation through the epigenetic regulator histone acetyl transferase EP300. Altogether, our work unveils unprecedented roles of CAF metabolism to support pro-tumorigenic collagen production. PYCR1 is a recognised cancer cell vulnerability and potential target for therapy, hence, our work provides evidence that targeting PYCR1 in tumours may have the additional benefit of halting the production of pro-tumorigenic ECM.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........141b63b9ae7495d04dd7471c8a4e8473
Full Text :
https://doi.org/10.1101/2020.05.30.125237