RT info:eu-repo/semantics/article
T1 Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix
A1 Hernández Fernaud, Juan Ramón
A1 Kay, Emily J.
A1 Paterson, Karla
A1 Riera-Domingo, Carla
A1 Sumpton, David
A1 Däbritz,  J. Henry M.
A1 Tardito, Saverio
A1 Boldrini, Claudia
A1 Athineos, Dimitris
A1 Dhayade, Sandeep
A1 Stepanova, Ekaterina
A1 Gjerga, Enio
A1 Neilson, Lisa J.
A1 Lilla, Sergio
A1 Hedley, Ann
A1 Koulouras, Grigorios
A1 McGregor, Grace
A1 Jamieson, Craig
A1 Johnson, Radia Marie
A1 Park, Morag
A1 Kirschner, Kristina
A1 Miller, Crispin
A1 Kamphorst, Jurre J.
A1 Loayza-Puch, Fabricio
A1 Sáez-Rodríguez, Julio
A1 Mazzone, Massimiliano
A1 Blyth, Karen
A1 Zagnoni, Michele
A1 Zanivan, Sara
A2 BioquímicaMicrobiología, Biología Celular y Genética
A2 The Beatson Institute for Cancer ResearchGlasgow, UK
AB Elevated production of collagen-rich extracellular matrix is a hallmark of cancer-associated fibroblasts (CAFs) and a centraldriver 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 synthesisand highly expressed in the stroma of breast cancer patients and in CAFs. Reducing PYCR1 levels in CAFs is sufficient to reducetumour collagen production, tumour growth and metastatic spread in vivo and cancer cell proliferation in vitro. Both collagenand glutamine-derived proline synthesis in CAFs are epigenetically upregulated by increased pyruvate dehydrogenase-derivedacetyl-CoA levels. PYCR1 is a cancer cell vulnerability and potential target for therapy; therefore, our work provides evidencethat targeting PYCR1 may have the additional benefit of halting the production of a pro-tumorigenic extracellular matrix. Ourwork unveils new roles for CAF metabolism to support pro-tumorigenic collagen production.
YR 2022
FD 2022
LK http://riull.ull.es/xmlui/handle/915/38876
UL http://riull.ull.es/xmlui/handle/915/38876
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 08-feb-2025