CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo
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
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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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 2

Conditional overexpression of CDCP1 initiates tumorigenesis.

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Conditional overexpression of CDCP1 initiates tumorigenesis. (A) Represe...
(A) Representative images of H&E staining of anterior prostate of WT and CDCP1 mice. Scale bars: 500 µm. Boxes represent regions in higher magnification in WT mice, prostatic intraepithelial neoplasia (PIN), and high-grade PIN (HGPIN) in CDCP1 mice. Scale bars: 125 µm. (B) Histopathological characterization and quantification of the prostate in WT and CDCP1 mice. (C) IHC staining of H&E and AR in representative anterior prostate gland of WT and CDCP1 mice affected by HGPIN. Scale bars: 300 μm. (D) IHC staining of Ki-67 in representative anterior prostate of WT and CDCP1 mice older than 10 months. Scale bars: 250 µm. Quantification of Ki-67 staining in anterior prostate of WT and CDCP1 mice at the indicated ages (n = 3–7 for each genotype). (E) Western blot analysis of major downstream targets of CDCP1 signaling in anterior prostates of 4-month-old WT and CDCP1 mice. Bar graph represents the fold change of normalized p-Akt, p-Erk1/2, and p-Src to their total proteins in CDCP1 prostates compared with WT prostates (n = 4). (F) Western blot analysis of major downstream targets of CDCP1 signaling in mouse embryonic fibroblasts (MEFs) from CDCP1 transgenic mice infected with retroviral vector overexpressing GFP or Cre. Bar graph represents the fold change of normalized p-Akt, p-Erk1/2, and p-Src to their total proteins in transgenic MEF-CDCP1 mice infected with GFP or Cre retro-virus vectors (n = 3). Error bars indicate SD. *P < 0.05; **P < 0.01; ***P < 0.001. Statistical test: 2-tailed t test.