Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix

Kay, E. J. et al. (2022) Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nature Metabolism, 4(6), pp. 693-710. (doi: 10.1038/s42255-022-00582-0) (PMID:35760868) (PMCID:PMC9236907)

Abstract

Elevated production of collagen-rich extracellular matrix is a hallmark of cancer-associated fibroblasts (CAFs) and a central driver of cancer aggressiveness. Here we find that proline, a highly abundant amino acid in collagen proteins, is newly synthesized from glutamine in CAFs to make tumour collagen in breast cancer xenografts. PYCR1 is a key enzyme for proline synthesis and highly expressed in the 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. Both collagen and glutamine-derived proline synthesis in CAFs are epigenetically upregulated by increased pyruvate dehydrogenase-derived acetyl-CoA levels. PYCR1 is a cancer cell vulnerability and potential target for therapy; therefore, our work provides evidence that targeting PYCR1 may have the additional benefit of halting the production of a pro-tumorigenic extracellular matrix. Our work unveils new roles for CAF metabolism to support pro-tumorigenic collagen production.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Blyth, Professor Karen and Lilla, Dr Sergio and Zanivan, Professor Sara and Hernandez, Dr Juan and Miller, Professor Crispin and Kay, Emily and Athineos, Mr Dimitris and McGregor, Grace and Tardito, Dr Saverio and Koulouras, Mr Grigorios and Sumpton, Mr David and Kamphorst, Dr Jurre and Kirschner, Dr Kristina and Neilson, Ms Lisa and Däbritz, Jan
• Authors: Kay, E. J., Paterson, K., Riero-Domingo, C., Sumpton, D., Däbritz, J. H. M., Tardito, S., Boldrini, C., Hernandez-Fernaud, J. R., Athineos, D., Dhayade, S., Stepanova, E., Gjerga, E., Neilson, L. J., Lilla, S., Hedley, A., Koulouras, G., McGregor, G., Jamieson, C., Johnson, R. M., Park, M., Kirschner, K., Miller, C., Kamphorst, J. J., Loayza-Puch, F., Saez-Rodriguez, J., Mazzone, M., Blyth, K., Zagnoni, M., and Zanivan, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Metabolism
• Publisher: Nature Research
• ISSN: 2522-5812
• ISSN (Online): 2522-5812
• Published Online: 27 June 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature Metabolism 4(6): 693-710
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190874		CR-UK Centre renewal	Karen Vousden	Cancer Research UK (CRUK)	C596/A18076	Institute of Cancer Sciences
306709		Early detection of pre-leukaemic clones in the aged haematopoietic compartment using single cell approaches	Kristina Kirschner	Leukaemia UK (LEUKA)	2019/JGF/003	CS - Epigenetics