PXD024746

PXD024746 is an original dataset announced via ProteomeXchange.

Title	Proteomic analysis of ECM-enriched fraction of breast xenograft and skin tissue from mice injected with 13C-glutamine
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-05-31
AnnouncementXML	Submission_2022-05-31_03:00:47.519.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sergio Lilla
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-15 08:25:48	ID requested
⏵ 1	2022-05-31 03:00:47	announced

Dataset with its publication pending

submitter keyword: Breast cancer, Collagen, xenograft tumour of MCF10DCIS.com

Sara Rossana Zanivan
contact affiliation	CRUK - Beatson Institute for Cancer Research - Switchback Rd, Bearsden, Glasgow G61 1BD - United Kingdom
contact email	s.zanivan@beatson.gla.ac.uk
lab head
Sergio Lilla
contact affiliation	Proteomics
contact email	s.lilla@beatson.gla.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/05/PXD024746

PRIDE project URI

• PRIDE
  1. PXD024746
     1. Label: PRIDE project
     2. Name: Proteomic analysis of ECM-enriched fraction of breast xenograft and skin tissue from mice injected with 13C-glutamine