Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
23
09
2021
accepted:
10
05
2022
entrez:
27
6
2022
pubmed:
28
6
2022
medline:
30
6
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35760868
doi: 10.1038/s42255-022-00582-0
pii: 10.1038/s42255-022-00582-0
pmc: PMC9236907
doi:
Substances chimiques
Glutamine
0RH81L854J
Collagen
9007-34-5
Proline
9DLQ4CIU6V
Pyrroline Carboxylate Reductases
EC 1.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
693-710Subventions
Organisme : Cancer Research UK
ID : A31287
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A18076
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A17196
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29800
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A23982
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29799
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
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