Proteomic analysis of ECM-enriched fraction of breast xenograft and skin tissue from mice injected with 13C-glutamine

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 has been shown to restrain but also promote cancer progression. Metabolic rewiring is a second hallmark of CAFs. 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 increased in breast cancer patient-derived CAFs compared to their matched normal fibroblasts in vitro. PYCR1 is the rate-limiting enzyme for proline synthesis and is highly expressed in the tumour stroma of breast cancer patients and in CAFs. Reducing PYCR1 levels in CAFs is sufficient to reduce collagen production, tumour growth and metastatic spread in vivo and cancer cell proliferation in vitro. Collagen and proline synthesis are enhanced by increased acetyl-CoA levels, which occurs through the epigenetic regulator EP300, and targeting PYCR1 overwrites this epigenetic reprogramming and decreases collagen production. Altogether, we present a previously uncharacterised pathway that supports pro-tumorigenic collagen production in CAFs. We show that PYCR1 and COL1A1 are overexpressed in patients with poor prognosis in several cancer types. PYCR1 is a recognised cancer cell vulnerability and potential target for therapy, hence, our work provides evidence that targeting PYCR1 in tumours may have the additional benefit of halting the production of pro-tumorigenic ECM. Finally, PYCR1 is highly expressed in collagen-producing fibroblasts derived from lungs of idiopathic pulmonary fibrosis patients, suggesting that PYCR1 may also offer therapeutic opportunities in fibrotic diseases.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Breast Cancer Cell

DISEASE(S): Breast Cancer

SUBMITTER: Sergio Lilla  

LAB HEAD: Sara Rossana Zanivan

PROVIDER: PXD024746 | Pride | 2022-05-31

REPOSITORIES: Pride