CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression

Abstract

The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving its treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP is highly expressed in advanced UC, which significantly correlates with shorter overall survivals. Importantly, the basal/squamous (Ba/Sq) UC subtype showed significantly enriched protein and mRNA levels for CDCP1. Moreover, ex-vivo organoids derived from CDCP1pcLSL/+ transgenic mouse model were used to assess the functional role of CDCP1 overexpression, while UC cell lines knockouts for CDCP1 were generated using CRISPR-Cas9-technology to model the effect of targeting CDCP1. Interestingly, CDCP1 overexpression significantly induced proliferation and activation of MAPK pathways in ex-vivo organoids. In addition, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK pathway activity reduction. Our results showed highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role in UC, suggesting that targeting CDCP1 could be a rational therapeutic strategy for advanced UC.