The diverse roles of CDCP1 in cancer and metabolism

CUB Domain Containing Protein 1 (CDCP1) is a transmembrane glycoprotein that has mainly been implicated in driving migration and metastasis of carcinoma cells. We focus on its role in triple-negative breast cancer (TNBC) metastasis, liver metabolic disorders (metabolic syndrome, non-alcoholic fatty liver disease, and type-2 diabetes mellitus), and wound healing. In TNBC cells, we uncovered a novel mechanism of CDCP1 activation via cleavage and homo-dimerization to promote trans-phosphorylation of its downstream target, PKCδ, by Src kinase. Furthermore, we uncovered a novel role of CDCP1 as a regulator of lipid metabolism in TNBC. We found that CDCP1 reduces cytoplasmic lipid droplet (LD) abundance and promotes fatty acid β-oxidation (FAO) in TNBC cells. We found that CDCP1 regulates lipid metabolism partially by reducing Acyl-CoA Synthetase Ligases (ACSLs). All of this leads to CDCP1-induced TNBC metastasis, which can be inhibited by blocking CDCP1 homo-dimerization via overexpression of the extracellular portion of cleaved CDCP1 (ECC). ECC reduces phosphorylation of PKCδ and increases ACSL activity and LD abundance in TNBC cells to reduce metastasis of TNBC tumors to the lungs. Physiologically, we found that CDCP1 regulates LD abundance in the livers of mice; CDCP1 knockout (KO) mice had higher LD abundance than CDCP1 heterozygous (Het) mice. We also found that CDCP1 KO mice had reduced wound healing capacity of dermal punch biopsy wounds compared to CDCP1 Het mice. Further, we present preliminary findings in the quest to identify important residues in CDCP1 dimerization and the development of a surrogate biomarker of CDCP1 activity in breast cancer. Combined, these studies give a comprehensive look at the broad range of pathological and physiological effects CDCP1 has and contributes groundwork for future investigation into these diverse and potentially organ-type specific roles of CDCP1