Identification of Master Transcriptional Regulators of Neuroendocrine Differentiation in Prostate Cancer

In healthy men, the prostate epithelium is made up of basal, luminal, and rare neuroendocrine cells. In prostate cancer, however, the luminal population expands in a manner that is dependent on androgens, which are male hormones secreted by the testicles. For this reason, since the 1940s, researchers have designed increasingly effective therapies to block androgen receptor (AR) function in prostate cells. However, despite the current ability to repress androgen levels to almost undetectable levels, nearly all patients will ultimately relapse, and in a fraction of cases, their tumor cells will acquire neuroendocrine features. Interestingly, the latest findings support a model in which some luminal cells can change their identity under therapeutic pressure, undergoing a process termed “transdifferentiation” to become neuroendocrine cells. By sequencing all genes active in mouse and human prostate cancers with neuroendocrine features, Dr. Michael Shen and his collaborators have recently identified about 40 putative molecular regulators of this transdifferentiation process. Here, I propose to screen this list of candidate genes by using two- and three-dimensional prostate cell cultures and combining advanced methods for editing gene function with high-through-put strategies for profiling cellular features. The main objective is identification of master regulators of neuroendocrine transdifferentiation in prostate cancer. The identification of a few key factors in this process, across the myriad of cellular molecules, represents the first key step toward the development of specific early detection or therapeutic strategies to prevent this deadly form of resistance. Throughout my early career path across three distinct research institutes in two different countries (Italy and the UK), I have researched fundamental biological mechanisms in stem cells, which are the cells that normally give rise to our healthy tissues, yet in some circumstances can be transformed into cells that give rise to cancer. By pursuing this project at Columbia University Medical Center (CUMC), under the supervision of Dr. Shen, I will learn how to apply cutting-edge, high-throughput technologies to tackle a complex biomedical problem. To do so, I will collaborate with experienced researchers across different disciplines within CUMC and in the broader academic community in New York City. Dr. Shen will also provide mentorship on how to best communicate and disseminate my science by writing articles in peer-reviewed journals, giving seminars at local/national/international conferences, and participating in outreach activities for the general public. Such training experience will provide me with experimental and organizational skills, as well as a publication track-record and a network of collaborators, which are necessary to compete for funding to start my own independent research group. At the present time, in patients suffering advanced forms of prostate cancer, it is not possible to detect progression toward neuroendocrine transdifferentiation (unless metastatic biopsies are performed), and even if recognized, no therapeutic strategy is available against the emergence of such a form of drug resistance. The successful completion of this project will lead to identification of one or more master regulators of neuroendocrine transdifferentiation that may serve as biomarkers for early detection of such tumors, as well as drug targets for future development of effective treatments. By unveiling the biological mechanisms of neuroendocrine transdifferentiation, I plan to open new avenues for extending the length and quality of life in men with a high risk of metastatic prostate cancer.