CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities

// Stephane Terry 1, 2, 3, 4 , Ihsan Y. El-Sayed 1, 2, 5 , Damien Destouches 1, 2, 6 , Pascale Maille 7 , Nathalie Nicolaiew 1, 2 , Guillaume Ploussard 1, 9 , Fannie Semprez 1, 2 , Cynthia Pimpie 1, 2 , Himisha Beltran 8 , Arturo Londono-Vallejo 3 , Yves Allory 1, 2, 7 , Alexandre de la Taille 1, 2, 9, * , David S. Salomon 10, * , Francis Vacherot 1, 2, * 1 Inserm, U955, Equipe 7, Creteil, France 2 Universite Paris-Est, UMR_S955, UPEC, F-94000, Creteil, France 3 Institut Curie, Centre de Recherche, CNRS UMR 3244, Paris, F-75248, France 4 Inserm, U753, Institut de Cancerologie Gustave Roussy, F-94805, Villejuif, France 5 EDST/PRASE, Rafic Harriri Campus, Faculte des Sciences, Universite Libanaise, Beyrouth, Liban 6 Laboratoire de Recherche sur la Croissance Cellulaire, la Reparation et la Regeneration Tissulaires (CRRET), CNRS, F-94010, Creteil, France 7 AP-HP, Hopital H. Mondor, Departement de pathologie, F-94000, Creteil, France 8 Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA 9 AP-HP, Hopital H. Mondor, Service d’urologie, F-94000, Creteil, France 10 Mouse Cancer Genetics Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA * These authors have contributed equally to this work Correspondence to: Stephane Terry, e-mail: stephane.terry@gmail.com Keywords: prostate cancer, CRIPTO, mesenchymal-like cancer cells, EMT, FGFR, AKT Received: August 15, 2014      Accepted: November 11, 2014      Published: January 22, 2015 ABSTRACT Members of the EGF-CFC (Cripto, FRL-1, Cryptic) protein family are increasingly recognized as key mediators of cell movement and cell differentiation during vertebrate embryogenesis. The founding member of this protein family, CRIPTO, is overexpressed in various human carcinomas. Yet, the biological role of CRIPTO in this setting remains unclear. Here, we find CRIPTO expression as especially high in a subgroup of primary prostate carcinomas with poorer outcome, wherein resides cancer cell clones with mesenchymal traits. Experimental studies in PCa models showed that one notable function of CRIPTO expression in prostate carcinoma cells may be to augment PI3K/AKT and FGFR1 signaling, which promotes epithelial-mesenchymal transition and sustains a mesenchymal state. In the observed signaling events, FGFR1 appears to function parallel to AKT, and the two pathways act cooperatively to enhance migratory, invasive and transformation properties specifically in the CRIPTO overexpressing cells. Collectively, these findings suggest a novel molecular network, involving CRIPTO, AKT, and FGFR signaling, in favor of the emergence of mesenchymal-like cancer cells during the development of aggressive prostate tumors.