Haworth, J. | Search bioRxiv

bioRxiv2023

Proteomics of Patient-derived Breast Tumours Identifies a Pro-migratory Osteomodulin-Cyclin Dependent Kinase 1 Axis which Drives Bone Metastasis

Metastasis to different organs remains the main cause of mortality in breast cancer. Molecular predictors of metastasis are limited as well as therapeutic options. Here, we conducted quantitative proteomics and phosphoproteomics analysis of patient-derived tumours, identifying osteomodulin (OMD) as a dysregulated protein and associated with bone metastases. Cancer-associated fibroblasts secrete OMD which increases breast cancer migration in vitro and promotes the formation of bone metastases in vivo. Downstream of OMD, phosphoproteomics identified the activation of cyclin-dependent kinase 1 (CDK1). The OMD-CDK1 signalling axis drives a pro-migratory and pro-survival phenotype in vitro and bone metastasis in vivo. Our findings highlight the importance of OMD and CDK1 in breast cancer bone metastasis and proposes an alternative therapeutic avenue for the treatment and the prevention of organ-specific metastases.

cancer biology↗

bioRxiv2020

DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity

ABSTRACTDysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this hallmark have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess fatty acids suppress growth factor signaling and cause oxidative stress in non-transformed cells, but surprisingly not in cancer cells. Molecules underlying this cancer adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, as a frequently up-regulated oncoprotein allowing cancer cells to tolerate excess fatty acids. DGAT1 over-expression alone induced melanoma in zebrafish melanocytes, and co-operated with oncogenic BRAF or NRAS for more rapid melanoma formation. Mechanistically, DGAT1 stimulated melanoma cell growth through sustaining mTOR kinase–S6 kinase signaling and suppressed cell death by tempering fatty acid oxidation, thereby preventing accumulation of reactive oxygen species including lipid peroxides.SIGNIFICANCE We show that DGAT1 is a bona fide oncoprotein capable of inducing melanoma formation and co-operating with other known drivers of melanoma. DGAT1 facilitates enhanced fatty acid acquisition by melanoma cells through suppressing lipototoxicity. DGAT1 is also critical for maintaining S6K activity required for melanoma cell growth.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗