ITGB1-dependent upregulation of Caveolin-1 switches TGF beta signalling from tumour-suppressive to oncogenic in prostate cancer

Caveolin-1 (CAV1) is over-expressed in prostate cancer (PCa) and is associated with adverse prognosis, but the molecular mechanisms linking CAV1 expression to disease progression are poorly understood. Extensive gene expression correlation analysis, quantitative multiplex imaging of clinical samples, and analysis of the CAV1-dependent transcriptome, supported that CAV1 re-programmes TGF beta signalling from tumour suppressive to oncogenic (i.e. induction of SLUG, PAI-1 and suppression of CDH1, DSP, CDKN1A). Supporting such a role, CAV1 knockdown led to growth arrest and inhibition of cell invasion in prostate cancer cell lines. Rationalized RNAi screening and high-content microscopy in search for CAV1 upstream regulators revealed integrin beta1 (ITGB1) and integrin associated proteins as CAV1 regulators. Our work suggests TGF beta signalling and beta1 integrins as potential therapeutic targets in PCa over-expressing CAV1, and contributes to better understand the paradoxical dual role of TGF beta in tumour biology.This study was supported by grants SAF2011-25047 and CSD2009-0016 from Spanish Ministry of Science and Innovation (MICINN), SAF2014-51876-R from Spanish Ministry of Economy and Competitiveness (MINECO) and co-funded by FEDER funds, 674/C/2013 from Fundacio La Marato de TV3, and AICR 15-0404 from the Worldwide Cancer Research Foundation (to M.A.dP.), by BIO2014-62200-EXP (to M.M.) as well as from the Academy of Finland Center of Excellence in Translational Cancer Biology (251314), Sigrid Juselius Foundation, and Cancer Society of Finland (to O.K.). T.P. was funded by CNIC Postdoctoral Program and by the Academy of Finland Post-doctoral fellow position (253662). Additional funding was from Emil Aaltonen foundation, Wihuri foundations, and Magnus Ehrnrooth foundation (to T.P.). Montserrat Arroyo (CNIC Cellomics Unit) helped in performing the screening. The CNIC is supported by MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S