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

被引：32

作者：

Alajati, Abdullah ^{[1
,2
]}

D'Ambrosio, Mariantonietta ^{[1
,2
,3
]}

Troiani, Martina ^{[1
,2
]}

Mosole, Simone ^{[1
,2
]}

Pellegrini, Laura ^{[1
,2
]}

Chen, Jingjing ^{[1
,2
,3
]}

Revandkar, Ajinkya ^{[1
,2
,3
]}

Bolis, Marco ^{[1
,2
]}

Theurillat, Jean-Philippe ^{[1
,2
]}

Guccini, Ilaria ^{[1
,2
]}

Losa, Marco ^{[1
,2
]}

Calcinotto, Arianna ^{[1
,2
]}

De Bernardis, Gaston ^{[1
,2
]}

Pasquini, Emiliano ^{[1
,2
]}

D'Antuono, Rocco ^{[4
]}

Sharp, Adam ^{[5
]}

Figueiredo, Ines ^{[5
,6
]}

Rodrigues, Daniel Nava ^{[5
,6
]}

Welti, Jonathan ^{[5
,6
]}

Gil, Veronica ^{[5
,6
]}

Yuan, Wei ^{[5
,6
]}

Vlajnic, Tatjana ^{[7
]}

Bubendorf, Lukas ^{[7
]}

Chiorino, Giovanna ^{[8
]}

Gnetti, Letizia ^{[9
]}

Torrano, Veronica ^{[10
,11
,12
]}

Carracedo, Arkaitz ^{[10
,11
,12
,13
]}

Camplese, Laura ^{[14
]}

Hirabayashi, Susumu ^{[14
]}

Canato, Elena ^{[15
]}

Pasut, Gianfranco ^{[15
]}

Montopoli, Monica ^{[15
]}

Ruschoff, Jan Hendrik ^{[16
]}

Wild, Peter ^{[16
]}

Moch, Holger ^{[16
]}

De Bono, Johann ^{[5
,6
]}

Alimonti, Andrea ^{[1
,2
,3
,17
,18
]}

机构：

[1] Oncol Inst Southern Switzerland IOSI, Inst Oncol Res IOR, Bellinzona, Switzerland

[2] Univ Svizzera Italiana, Lugano, Switzerland

[3] Univ Lausanne UNIL, Fac Biol & Med, Lausanne, Switzerland

[4] Inst Res Biomed IRB, Bellinzona, Switzerland

[5] Inst Canc Res, Div Clin Studies, London, England

[6] Royal Marsden NHS Fdn Trust, London, England

[7] Univ Hosp Basel, Inst Pathol, Basel, Switzerland

[8] Fdn Edo & Elvo Tempia, Via Malta, Biella, Italy

[9] Univ Hosp Parma, Pathol Unit, Parma, Italy

[10] Basque Res & Technol Alliance BRTA, Ctr Cooperat Res Biosci CIC BioGUNE, Derio, Spain

[11] Univ Basque Country UPV EHU, Biochem & Mol Biol Dept, Bilbao, Spain

[12] Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain

[13] Ikerbasque Basque Fdn Sci, Bilbao, Spain

[14] Imperial Coll London, MRC London Inst Med Sci LMS, London, England

[15] Univ Padua, Dept Pharmaceut & Pharmacol Sci, Padua, Italy

[16] Univ Hosp Zurich, Inst Pathol & Mol Pathol, Zurich, Switzerland

[17] Univ Padua, Dept Med, Padua, Italy

[18] Eidgenoss Tech Hsch Zurich ETH, Dept Hlth Sci & Technol, Zurich, Switzerland

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 05期

基金：

欧洲研究理事会; 瑞士国家科学基金会; 英国医学研究理事会; 欧盟地平线“2020”;

关键词：

DOMAIN-CONTAINING PROTEIN-1; SURFACE GLYCOPROTEIN CDCP1; PTEN LOSS; RECEPTOR; MECHANISMS; EXPRESSION; METASTASIS; RESISTANCE; GROWTH; SRC;

D O I：

10.1172/JCI131133

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：2435 / 2450

页数：16

共 57 条

[11] Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer [J].

Carver, Brett S. ;

Chapinski, Caren ;

Wongvipat, John ;

Hieronymus, Haley ;

Chen, Yu ;

Chandarlapaty, Sarat ;

Arora, Vivek K. ;

Le, Carl ;

Koutcher, Jason ;

Scher, Howard ;

Scardino, Peter T. ;

Rosen, Neal ;

Sawyers, Charles L. .

CANCER CELL, 2011, 19 (05) :575-586

[12] Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process [J].

Chandran, Uma R. ;

Ma, Changqing ;

Dhir, Rajiv ;

Bisceglia, Michelle ;

Lyons-Weiler, Maureen ;

Liang, Wenjing ;

Michalopoulos, George ;

Becich, Michael ;

Monzon, Federico A. .

BMC CANCER, 2007, 7 (1)

[13] Mechanisms of resistance in castration-resistant prostate cancer (CRPC) [J].

Chandrasekar, Thenappan ;

Yang, Joy C. ;

Gao, Allen C. ;

Evans, Christopher P. .

TRANSLATIONAL ANDROLOGY AND UROLOGY, 2015, 4 (03) :365-380

[14] Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis [J].

Chen, ZB ;

Trotman, LC ;

Shaffer, D ;

Lin, HK ;

Dotan, ZA ;

Niki, M ;

Koutcher, JA ;

Scher, HI ;

Ludwig, T ;

Gerald, W ;

Cordon-Cardo, C ;

Pandolfi, PP .

NATURE, 2005, 436 (7051) :725-730

[15] BRAF and KRAS mutations in prostatic adenocarcinoma [J].

Cho, Nam-Yun ;

Choi, Minhee ;

Kim, Baek-Hee ;

Cho, Yong-Mee ;

Moon, Kyung Chul ;

Kang, Gyeong Hoon .

INTERNATIONAL JOURNAL OF CANCER, 2006, 119 (08) :1858-1862

[16] Cancer genetics-guided discovery of serum biomarker signatures for diagnosis and prognosis of prostate cancer [J].

Cima, Igor ;

Schiess, Ralph ;

Wild, Peter ;

Kaelin, Martin ;

Schueffler, Peter ;

Lange, Vinzenz ;

Picotti, Paola ;

Ossola, Reto ;

Templeton, Arnoud ;

Schubert, Olga ;

Fuchs, Thomas ;

Leippold, Thomas ;

Wyler, Stephen ;

Zehetner, Jens ;

Jochum, Wolfram ;

Buhmann, Joachim ;

Cerny, Thomas ;

Moch, Holger ;

Gillessen, Silke ;

Aebersold, Ruedi ;

Krek, Wilhelm .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (08) :3342-3347

[17]

Culí J, 2001, DEVELOPMENT, V128, P299

[18] Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer [J].

Di Mitri, Diletta ;

Toso, Alberto ;

Chen, Jing Jing ;

Sarti, Manuela ;

Pinton, Sandra ;

Jost, Tanja Rezzonico ;

D'Antuono, Rocco ;

Montani, Erica ;

Garcia-Escudero, Ramon ;

Guccini, Ilaria ;

Da Silva-Alvarez, Sabela ;

Collado, Manuel ;

Eisenberger, Mario ;

Zhang, Zhe ;

Catapano, Carlo ;

Grassi, Fabio ;

Alimonti, Andrea .

NATURE, 2014, 515 (7525) :134-+

[19] SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression [J].

Ding, Zhihu ;

Wu, Chang-Jiun ;

Chu, Gerald C. ;

Xiao, Yonghong ;

Ho, Dennis ;

Zhang, Jingfang ;

Perry, Samuel R. ;

Labrot, Emma S. ;

Wu, Xiaoqiu ;

Lis, Rosina ;

Hoshida, Yujin ;

Hiller, David ;

Hu, Baoli ;

Jiang, Shan ;

Zheng, Hongwu ;

Stegh, Alexander H. ;

Scott, Kenneth L. ;

Signoretti, Sabina ;

Bardeesy, Nabeel ;

Wang, Y. Alan ;

Hill, David E. ;

Golub, Todd R. ;

Stampfer, Meir J. ;

Wong, Wing H. ;

Loda, Massimo ;

Mucci, Lorelei ;

Chin, Lynda ;

DePinho, Ronald A. .

NATURE, 2011, 470 (7333) :269-+

[20]

Dodson GS, 1998, DEVELOPMENT, V125, P2883

← 1 2 3 4 5 6 →