Abstract Caveolin-1 (Cav1) can have both a tumor suppressive or promoting role depending on cancer tissue, and its potential active role in the progression of prostate cancer remains poorly understood. In this study, we found out that Cav1 represses the expression of E-cadherin in prostate cancer cell lines, and that the expressions of these two genes show an inverse correlation both at the mRNA and protein levels in PCa patient samples. We show that the combined loss of E-cadherin and gain of Cav1 expression is an early event in a subgroup of patients (<10%) (n(patients) = 80, n(glands) = 263, r = -0.35, p<0.001). Cav1 positively regulates TGFβ targets with known oncogenic and pro-EMT functions (e.g. Slug, Pai-1), and its absence switches the TGFβ to become inhibitory to PCa cells by inducing p21 (CDKN1A) and STAT1 signaling. These changes were strongly associated with changes in 3D-invasive growth. By using RNAi image-based screening, we found out that Cav1 is positively regulated by beta1-integrins and cell adhesion to ECM. This association together with different alpha-integrins was visualized and quantified in human prostate cancer patient tissues (n = 80) using novel multiplexed fluorescent imaging. Both the integrin beta1 and alpha2 showed high correlation with Cav1 expression (p-values<0.001) in tumor epithelium as well as in stroma. In conclusion, the results suggest that Cav1 could be an important promoter of invasive growth in a subgroup of PCa, where it is upregulated by beta1-integrins, and where it promotes oncogenic TGFβ signaling. Citation Format: Teijo Pellinen, Sami Blom, Sara Sanches, Katja Välimäki, John-Patrick Mpindi, Antti Rannikko, Raffaele Strippoli, Maria Montoya, Hind Azegrouz, Tuomas Mirtti, Miguel del Pozo, Olli Kallioniemi. Caveolin-1 drives oncogenic TGFβ effects in prostate cancer: in vitro mechanistic insights integrated with systems pathology visualization in primary tumor samples. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 207. doi:10.1158/1538-7445.AM2015-207