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

Kay, Emily J and Paterson, Karla and Riero-Domingo, Carla and Sumpton, David and Daebritz, Henry and Tardito, Saverio and Boldrini, Claudia and Hernandez-Fernaud, Juan R and Athineos, Dimitris and Dhayade, Sandeep and Stepanova, Ekaterina and Gjerga, Enio and Neilson, Lisa J and Lilla, Sergio and Hedley, Ann and Koulouras, Grigorios and McGregor, Grace and Jamieson, Craig and Johnson, Radia Marie and Park, Morag and Kirschner, Kristina and Miller, Crispin and Kamphorst, Jurre J. and Loayza-Puch, Fabricio and Saez-Rodriguez, Julio and Mazzone, Massimiliano and Blyth, Karen and Zagnoni, Michele and Zanivan, Sara (2022) PYCR1-dependent proline synthesis in cancer associated fibroblasts is required for the deposition of pro-tumorigenic extracellular matrix. Nature Metabolism. (In Press)

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Abstract

Elevated 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 can restrain but also promote cancer progression. 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 mammary CAFs. 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 enhanced by increased pyruvate dehydrogenase-derived acetyl-CoA levels, via gene expression regulation through the epigenetic regulator histone acetyl-transferase EP300. Our work unveils unprecedented roles of CAF metabolism to support pro-tumorigenic collagen production. PYCR1 is a cancer cell vulnerability and potential target for therapy, hence our work provides evidence that targeting PYCR1 may have the additional benefit of halting the production of pro-tumorigenic ECM.

ORCID iDs

Kay, Emily J, Paterson, Karla, Riero-Domingo, Carla, Sumpton, David, Daebritz, Henry, Tardito, Saverio, Boldrini, Claudia, Hernandez-Fernaud, Juan R, Athineos, Dimitris, Dhayade, Sandeep, Stepanova, Ekaterina, Gjerga, Enio, Neilson, Lisa J, Lilla, Sergio, Hedley, Ann, Koulouras, Grigorios, McGregor, Grace, Jamieson, Craig ORCID logoORCID: https://orcid.org/0000-0002-6567-8272, Johnson, Radia Marie, Park, Morag, Kirschner, Kristina, Miller, Crispin, Kamphorst, Jurre J., Loayza-Puch, Fabricio, Saez-Rodriguez, Julio, Mazzone, Massimiliano, Blyth, Karen, Zagnoni, Michele ORCID logoORCID: https://orcid.org/0000-0003-3198-9491 and Zanivan, Sara;
CORE (COnnecting REpositories)