Elucidating the stromal contribution of androgen deprivation therapy-resistance in prostate cancer

In my PhDproject, I will investigate the role of Cancer-Associated Fibroblasts (CAFs) in promoting castration-resistant and metastatic prostate cancer (PCa) to support the idea that not only tumor cells but also components of the tumor microenvironment (also known as ‘reactive stroma’) can be targeted to halt tumor progression. To purse this aim, three different PCa patient-derived xenograft(PDX) models will be used, representing androgen-dependent soft tissue metastasis (PNPCa model), androgen-dependent bone metastasis (BM18) and androgen-independent bone metastasis (LAPC9). Gene expression profiling of the tumor and stromal components of these PDXs in androgen intact and castrated settings will be analyzed. Furthermore, PDX-derived tumor cells will be combined with PDX-derived fibroblasts, as well as patient-derived CAFs, to establish 3D co-cultures (tumor-stromal organoids). These in vitro models will be used to characterize the role of CAFs in promoting tumor organoid growth and drug resistance, as well as gene expression alterations occurring in tumor and stromal cells. The ultimate goal of this project is to identify stromal genes/pathways that could represent novel therapeutic targets in PCa.

Francesco Bonollo