Pro-tumor and prothrombotic activities of hepsin in colorectal cancer cells and suppression by venetoclax

Hepsin is a type II transmembrane serine protease whose expression has been linked to greater tumorigenicity and worse prognosis in different tumors such as prostate and gastric cancer. Recently, our group described hepsin expression in the primary biopsy as a potential biomarker of thrombosis and metastasis in localized colorectal cancer patients. Here we explored the role of hepsin in this tumor. Hepsin overexpression increased Caco-2 cell migration and invasion, higher phosphorylation of Erk1/2 and STAT3 and led to more thrombin generation in plasma. Indeed, our study revealed higher plasma levels of hepsin in metastatic colorectal cancer patients, which was associated with a greater tendency toward thrombosis. By virtual screening of a FDA-approved drug library, we identified venetoclax as a potent hepsin inhibitor, reducing the metastatic and prothrombotic phenotype of Caco-2 cells, but not of other colorectal cancer cells without hepsin expression. Interestingly, pre-treating Caco-2 cells overexpressing hepsin with venetoclax reduced its in vivo invasiveness. Taken together, our results demonstrate that elevated hepsin levels correlate with a more aggressive and prothrombotic tumor phenotype. Likewise, they evidence an antitumor role for venetoclax as a hepsin inhibitor. This lays the groundwork for molecular targeted therapy for colorectal cancer. ### Competing Interest Statement The authors have declared no competing interest. * CI : cumulative incidence CRC : colorectal cancer DAPI : 4’, 6-diamino-2-phenylindole EdU : 5-ethynyl-2’-deoxyuridine EGFR : epidermal growth factor receptor Erk1/2 : extracellular signal-regulated kinases ETP : endogenous thrombin potential HPN : hepsin gene IC50 : half maximal inhibitory concentration KRAS : Kirsten Rat Sarcoma Viral Oncogene Homologue STAT3 : signal transducer and activator of transcription 3 TTSPs : type II transmembrane serine proteases VS : virtual screening