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CDCP1 initiates tumorigenesis and cooperates with PTEN loss to promote senescence evasion and prostate cancer progression

      Background: Elevated levels of CUB domain-containing protein 1 (CDCP1) have been reported to be associated with poor prognosis in several human malignancies, including prostate cancer. However, its oncogenic role remains unexploited. Taking an advantage of multiple cross species genetic models, we demonstrate that CDCP1 per se is an oncogene. Particularly in mice, overexpression of CDCP1 in prostatic epithelial cells initiates hyperplasia, which eventually develops high-grade prostatic intraepithelial neoplasia. The functional importance of CDCP1 in tumuorigenesis was further fortified based on the evident display of invasive and metastatic prostate tumors upon its overexpression concomitantly with loss of Pten in mouse prostates. Mechanistically, we demonstrate that CDCP1 leads to the activation of SRC that further enhances the level of the transcription factor c-Myc in vivo. In turn, enhanced Myc triggers transcriptional activation of Cyclin D1 and COUP transcription factor II (COUPTF-II) that bypasses the TGF-β-dependent checkpoint and senescence barrier driven by Pten-loss. Following on, we demonstrate that targeting CDCP1 antagonizes c-Myc expression to block tumourigenesis by reactivating cellular senescence in human prostate cancer cells.
      Methods: CDCP1, transgenic mouse model, PTEN, prostate cancer.
      Results: -Conditional overexpression of CDCP1 promotes tumourigenesis in different transgenic model systems -CDCP1 cooperates with Pten-loss in driving full malignant prostate tumourigenesis -Overexpression of CDCP1 overcomes Pten- loss induced cellular senescence by activating Myc-Targeting CDCP1 induces cellular senescence and growth arrest by downregulating Myc.
      Conclusions: In sum, our findings highlight a crucial role for CDCP1 in 1) driving tumourigeneis in several transgenic models and 2) inducing full malignant progression of Pten-null prostate tumourigenesis by eliciting an oncogenic and tumour suppressive network that results in senescence evasion and metastasis. As CDCP1 is a cell surface protein which can be targeted by currently available monoclonal antibodies, our study also put forth a novel therapeutic strategy to target SRC and MYC tumours in metastatic human prostate cancer.
      Legal entity responsible for the study: IOR-Bellinzona- Andrea Alimonti
      Funding: None
      Disclosure: All authors have declared no conflicts of interest.