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.
View: Text | PDF
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

×

Figure 3

CDCP1 cooperates with Pten loss to drive prostate cancer progression and metastasis.

Options: View larger image (or click on image) Download as PowerPoint
CDCP1 cooperates with Pten loss to drive prostate cancer progression and...
(A) Representative images of H&E staining of anterior prostate of WT, CDCP1, Ptenpc–/–, and CDCP1 Ptenpc–/– mice at the age of 10 months. Scale bars: 500 μm. Bar graph representing the percentage of mice with PIN, HGPIN, ADS-focal, and invasive PCa. (B) Bar graph representing tumor weight of Ptenpc–/– and CDCP1 Ptenpc–/– mice, insets represent anterior prostate of Ptenpc–/– and CDCP1 Ptenpc–/–. Scale bar: 1 cm. (C) Representatives images of H&E, Pan-cytokeratin (PanK), CDCP1, and AR staining of lumbar lymph node metastases in CDCP1 Ptenpc–/– mice at 10 months of age (n = 4/8). Scale bars: 250 μm. Graph shows the percentage of mice with lymph node and lung metastasis. (D) Cumulative survival of WT, CDCP1, Ptenpc–/–, and CDCP1 Ptenpc–/– mice. (E) Representative images of Ki-67 staining in anterior prostate of WT, CDCP1, Ptenpc–/–, and CDCP1 Ptenpc–/– mice (3 months old). Scale bars: 125 μm. Quantification of Ki-67 staining in anterior prostate of indicated genotypes (n = 3–4 for each genotype). (F) Western blot analysis and protein fold change quantification of specified proteins in anterior prostate glands from the indicated genotypes at 20 weeks of age. Graphs show protein fold change quantification of p-Src, p-Erk1/2, p-Akt, and c-Myc (n = 5–7). (G) Immunohistochemistry staining of p-AKT, p-ERK1/2, and c-Myc of anterior prostates of WT, CDCP1, Ptenpc–/–, and CDCP1 Ptenpc–/– mice. Scale bars: 300 μm (p-AKT, p-ERK1/2); 200 μm (c-Myc); 50 μm (inset). Error bars indicate SD for B and E and SEM for F. *P < 0.05; **P < 0.01; ***P < 0.001. The following statistical tests were used: unpaired 2-tailed t test for B and E, log-rank (Mantel-Cox) test for D, and 1-tailed t test for F.