PXD008276-1

PXD008276 is an original dataset announced via ProteomeXchange.

Title	Cancer Associated Fibroblast-FAK regulates malignant cell metabolism
Description	Breast and pancreatic cancers are characterised by profound metabolic changes1,2. Until recently, these changes have been ascribed to their intrinsic genetic profiles2-4. However, the contribution of cancer-associated fibroblasts (CAFs) to cell metabolism has not been fully investigated5. Here, we provide clinical evidence that reduction in stromal Focal Adhesion Kinase (FAK) correlates with reduced overall survival in human breast and pancreatic cancer patients. To model this, we developed FSP-Cre+;FAKfl/fl mice where FAK was deleted in a subpopulation of CAFs. We establish that loss of CAF-FAK is sufficient to enhance tumour growth without affecting desmoplasia in orthotopically injected breast and pancreatic carcinomas. Additionally, deletion of CAF-FAK enhances disease progression in the MMTV-PyMT spontaneous model of breast cancer. Furthermore, despite this pro-tumourigenic effect, a significant reduction in tumour angiogenesis was observed in late-stage tumours, but not early-stage, size-matched tumours in FSP-Cre+;FAKfl/fl mice. This indicates that loss of CAF-FAK is sufficient to reduce malignant cell dependency on blood vessel support suggesting acquired metabolic alterations in cancer cells. Indeed, 18F-FDG-PET imaging and glucose flux analysis revealed enhanced glucose catabolism in early-stage, size-matched tumours in FSP-Cre+;FAKfl/fl mice in vivo. Mechanistically, we demonstrate that conditioned medium from FAK-null CAFs enhances glycolysis and glycolytic capacity in malignant cells. Proteomics and phosphoproteomics analysis reveal enriched cytokine-mediated signalling pathways in FAK-null CAFs and subsequent enrichment of associated phosphopeptides in malignant cells, respectively. Overall, our data uncover a novel mechanism by which cytokines, regulated by CAF-FAK, can promote cancer growth and progression, and identify a new set of CAF-derived targets to interfere with cancer metabolism.
HostingRepository	PRIDE
AnnounceDate	2020-02-18
AnnouncementXML	Submission_2020-02-18_03:23:04.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD008276
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Pedro Casado-Izquierdo
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; deaminated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-11-23 01:17:11	ID requested
⏵ 1	2020-02-18 03:23:05	announced

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: FAK, Fibroblast, Metabolism

Pedro R. Cutillas
contact affiliation	Centre for Haemato-oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M6BQ, UK
contact email	p.cutillas@qmul.ac.uk
lab head
Pedro Casado-Izquierdo
contact affiliation	Cell Signalling
contact email	p.m.casado-izquierdo@qmul.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD008276
     1. Label: PRIDE project
     2. Name: Cancer Associated Fibroblast-FAK regulates malignant cell metabolism