Metastatic prostate cancer (PCa) and the development of CRPC are the major causes of mortality in PCa patients. The poor prognosis and failure of therapies in metastatic PCa could be associated to the heterogeneous nature of tumor cells. We previously showed that S100A4 protein drives the metastasis of PCa in preclinical models. On the basis of recent genomic data of >1000 patients, we now provide evidence that S100A4 in association with CD52 forms a unique and aggressive class of PCa in patients. The tumor genome data of patients show a direct correlation between S100A4 and CD52, a small glycoprotein expressed on T, B, NK, dendritic cells and monocytes. We posit that aggressive type of PCa cells during progression acquire immunosuppressive properties. Here, by employing a progressive panel of human PCa cell lines and primary prostate tumors and metastatic tumors, we show the presence of a subpopulation of PCa cells that express high levels of CD52 and S100A4. We were successful in isolating CD52+/S100A4+ subpopulation of aggressive PCa cells from DU145 (brain metastasis model) and PC3 (bone metastasis model). On analysis the CD52+/S100A4+ metastatic cells exhibited higher degree of invasiveness than the parental cells. These cells are characterized by the high expression of S100A4, VEGF and MMP9, phosphorylated-NFκB-p65 and phosphorylated-ERK. By using IHC, we observed that metastatic tumors

(brain, bone, testis) exhibiting high S100A4 levels also exhibited high expression of CD52. A marked increase in the number of CD52+/S100A4+ metastatic PCa cells were found in brain in patient Met specimens, that well explains the increased number of such tumor cell types found in DU145 model (isolated from brain). We provide data showing that genetic suppression CD52 (by using siRNA) significantly reduces the growth, migration and invasive potential of metastatic cells. However, suppressing CD52 has no bearing on S100A4 expression. On the contrary, modulation of S100A4 expression could bring changes in the expression of CD52 in PCa cells. These data suggest a potential link between the S100A4 and immunosuppressive type PCa cells human disease. In conclusion, the novelty of this study is that we for the first time identified a new PCa subtype that is aggressive and resistant to existing therapies. Another novel finding is that we identified CD52 as a novel target for treating metastatic PCa. These findings warrant future clinical studies in investigating CD52+/S100A4+ signature as a biopsy biomarker to identify patients (at diagnosis) who are prone to develop metastasis (particularly bone metastasis). In addition our data opens the opportunity to develop new therapies targeting CD52/S100A4 for treating aggressive metastatic PCa which otherwise remains a non-treatable disease. Grant Support: R01CA193739

Citation Format: Adrian Pablo Mansini, Marina G. Ferrari, Arsheed Ganaie. Identifying a novel and aggressive CD52+ve type of prostate cancer: Phenotype distinguishing biomarker and therapeutic target [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 343.