CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo
Abdullah Alajati, … , Johann De Bono, Andrea Alimonti
Abdullah Alajati, … , Johann De Bono, Andrea Alimonti
Published April 6, 2020
Citation Information: J Clin Invest. 2020;130(5):2435-2450. https://doi.org/10.1172/JCI131133.
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Research Article Oncology

CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo

Abstract

The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti–CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.

Authors

Abdullah Alajati, Mariantonietta D’Ambrosio, Martina Troiani, Simone Mosole, Laura Pellegrini, Jingjing Chen, Ajinkya Revandkar, Marco Bolis, Jean-Philippe Theurillat, Ilaria Guccini, Marco Losa, Arianna Calcinotto, Gaston De Bernardis, Emiliano Pasquini, Rocco D’Antuono, Adam Sharp, Ines Figueiredo, Daniel Nava Rodrigues, Jonathan Welti, Veronica Gil, Wei Yuan, Tatjana Vlajnic, Lukas Bubendorf, Giovanna Chiorino, Letizia Gnetti, Verónica Torrano, Arkaitz Carracedo, Laura Camplese, Susumu Hirabayashi, Elena Canato, Gianfranco Pasut, Monica Montopoli, Jan Hendrik Rüschoff, Peter Wild, Holger Moch, Johann De Bono, Andrea Alimonti

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Figure 1

Advanced and metastatic prostate tumors exhibit elevated expression of CDCP1 and overexpression of CDCP1 correlate with PTEN loss.

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Advanced and metastatic prostate tumors exhibit elevated expression of C...
(A) Representative images of IHC staining of CDCP1 in benign prostate hyperplasia (BPH), CRPC, and distant metastasis of PCa in human prostate cancer TMA1. Scale bar: 300 μm. (B) Percentage of CDCP1-positive samples in BPH, preradical prostatectomy (RPE), CRPC, and metastatic PCa in human prostate cancer TMA1 (n = 564). (C) Representative images of IHC staining of CDCP1 and PTEN in 2 different PCa patients. Scale bar: 300 μm. (D) Pie graph showing the percentage of PTEN-high/CDCP1–, PTEN-high/CDCP1–, PTEN-high/CDCP1+, PTEN-low/CDCP1– and PTEN-low/CDCP1+ in primary tumors and CRPC/metastasis. (E) Association of PTEN genomic loss to CDCP1 gene expression in TCGA (left panel) and Taylor data set (right panel) (5). Error bars indicate SEM; statistical test: Kruskal-Wallis. (F) Association of PTEN and CDCP1 expression levels with disease-free survival in the indicated patient data sets. In the Taylor data set, low PTEN indicates patients with expression signal lower than 8.74, and high CDCP1 indicates patients with expression signal higher than 11.19. In TCGA, low PTEN indicates patients with expression signal lower than 10.19, and high CDCP1 indicates patients with expression signal higher than 9.49. HR, hazard ratio. Statistical test: Mantel-Cox.