Blocking of CDCP1 In Vivo Cleavage Presents Akt‐Dependent Survival of Cancer Cells and Inhibits Their Metastatic Colonization via PARP1‐Mediated Apoptosis

The CUB domain‐containing protein 1 (CDCP1) is a transmembrane molecule implicated in cancer progression. We have established a novel mechanism for CDCP1‐induced signaling in vivo and demonstrated that specific processing of cell surface CDCP1 by an extracellular serine protease is a prerequisite for CDCP1‐mediated survival of cancer cells during metastasis. The in vivo cleavage of CDCP1 triggers a multistep signaling cascade involving activation of Src, Src phosphorylation of membrane‐retained CDCP1 fragment and CDCP1‐associated PKCδ, and activation of Akt, ultimately increasing tumor cell survival. Preventing the in vivo cleavage of CDCP1 with unique anti‐CDCP1 antibodies, serine protease inhibitors or genetic modulation of the cleavage site in the CDCP1 molecule completely abrogated survival signaling and induced PARP1‐mediated apoptosis, resulting in a substantial inhibition of metastatic colonization. In plasminogen knockout mice, the complete lack of CDCP1 cleavage was accompanied by the reduction of tumor cell survival, which were both rescued by in vivo supplied plasmin, indicating that plasmin is the crucial serine protease executing cleavage of CDCP1 during tissue colonization. Together, our findings indicate that in vivo blocking of CDCP1 cleavage upstream of CDCP1‐induced pro‐survival signaling provides a potential mechanism for therapeutic intervention into metastatic disease.