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

Kay, Emily J. and Paterson, Karla and Riero-Domingo, Carla and Sumpton, David and Däbritz, J. Henry M 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) Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nature metabolism, 4 (6). pp. 693-710. ISSN 2522-5812 (https://doi.org/10.1038/s42255-022-00582-0)

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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.

ORCID iDs

Kay, Emily J., Paterson, Karla, Riero-Domingo, Carla, Sumpton, David, Däbritz, J. Henry M, 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)