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

Autor: Kay EJ; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Paterson K; Centre for Microsystems and Photonics, EEE Department, University of Strathclyde, Glasgow, UK., Riera-Domingo C; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium., Sumpton D; Cancer Research UK Beatson Institute, Glasgow, UK., Däbritz JHM; Cancer Research UK Beatson Institute, Glasgow, UK., Tardito S; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Boldrini C; Cancer Research UK Beatson Institute, Glasgow, UK., Hernandez-Fernaud JR; Cancer Research UK Beatson Institute, Glasgow, UK., Athineos D; Cancer Research UK Beatson Institute, Glasgow, UK., Dhayade S; Cancer Research UK Beatson Institute, Glasgow, UK., Stepanova E; Translational Control and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany., Gjerga E; Heidelberg University, Faculty of Medicine, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany.; RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany., Neilson LJ; Cancer Research UK Beatson Institute, Glasgow, UK., Lilla S; Cancer Research UK Beatson Institute, Glasgow, UK., Hedley A; Cancer Research UK Beatson Institute, Glasgow, UK., Koulouras G; Cancer Research UK Beatson Institute, Glasgow, UK., McGregor G; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Jamieson C; Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, Glasgow, UK., Johnson RM; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada., Park M; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.; Department of Biochemistry, McGill University, Montreal, Quebec, Canada.; Department of Medicine, McGill University, Montreal, Quebec, Canada.; Department of Oncology, McGill University, Montreal, Quebec, Canada., Kirschner K; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Miller C; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Kamphorst JJ; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Loayza-Puch F; Translational Control and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany., Saez-Rodriguez J; Heidelberg University, Faculty of Medicine, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany.; RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany., Mazzone M; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium., Blyth K; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Zagnoni M; Centre for Microsystems and Photonics, EEE Department, University of Strathclyde, Glasgow, UK., Zanivan S; Cancer Research UK Beatson Institute, Glasgow, UK. s.zanivan@beatson.gla.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. s.zanivan@beatson.gla.ac.uk.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2022 Jun; Vol. 4 (6), pp. 693-710. Date of Electronic Publication: 2022 Jun 27.
DOI: 10.1038/s42255-022-00582-0
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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