FUNCTIONAL ATLAS OF PROSTATE CANCER MESENCHYME: A TRANSLATIONAL APPROACH TO DECIPHER THE STROMAL MOLECULAR LANDSCAPE IN PROSTATE CANCER INITIATION, PROGRESSION, AND METASTATIZATION. ​

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second-leading cause of cancer death. It has a heterogeneous prognosis with many patients with an indolent course and others with aggressive and potentially deadly disease. The differentiation of these patients remains a challenge and actual risk stratification leads to a significant overtreatment/undertreatment of some patients. Therefore there is a certain need for better prognostic tools to aid in the prediction of which patients will benefit from curative treatment. Most biomarker studies, have focused on molecular background of the PCa epithelium. However, PCa create a micro-ecosystems in which both cancer and stromal cells co-evolve, hence tumor microenvironment could likely provide additional predictive and prognostic information also in occult high-grade disease missed at biopsy. To date only few human studies have focused on stroma. In the present project has been performed a gene expression profiling of laser capture microdissected stroma surrounding benign, high grade intraepithelial neoplasia (PIN) and invasive PCa from low-and high-Gleason PCa radical proctectomies specimens as well as from stromal cells from normal prostates without cancer (cystoprostatectomy samples). The found stromal gene signature reflects the upregulation of bone remodeling and immune-related pathways in high compared to low-Gleason grade cases. Additionally, stroma away from tumor was significantly different from that in prostates without cancer. The obtained stromal gene signature has been validated on publicly available data and on in-vivo and in-vitro models demonstrating the ability to stratify patients according the increased risk of metastasis development and highlighting the potential drug-targetable pathways. These data corroborate the hypothesis that microenvironment may influence prostate cancer initiation, maintenance, metastatic progression and chemoresistance.