Project Summary and Abstract: Prostate cancer (PCa) is the most frequent cancer in American men. Luminal histology is a hallmark of PCa. Hormone therapy effectively targets luminal cells, but resistance inevitably occurs. The ERG oncoprotein is overexpressed in half of PCa cases. Prostatic ERG expression in mice recapitulates invasion with a luminal program seen in human PCa, thus presenting a clinically relevant model to study PCa. However, the molecular mechanisms by which ERG drives a luminal fate and invasive PCa remain unclear, insights from which may reveal new treatment paradigms. Project objective: To elucidate the mechanisms and vulnerabilities of ERG-driven luminal fate and PCa invasion. Preliminary data: 1) pseudo-basal cells (those with a mixture basal/luminal marker profile) rather than luminal cells are the most proliferative, and invasion-associated population in PCa; 2) a genome-wide CRISPR screen reveals that ERG stimulates luminal fate by alleviating aryl-hydrocarbon receptor (AHR) signaling, which provides a druggable vulnerability. Central hypothesis: ERG stimulates a progenitor state, characterized as pseudo-basal cells, that sustains invasion and luminal output of PCa. The proposed project leverages innovative mouse and organoid models, genome-wide screen data, and patient samples to test this hypothesis. Specific Aims: 1) determine the luminal progenitor and oncogenic potential of pseudo-basal cells in ERG-driven PCa; 2) define how AHR and other screen candidates modulate lineage output as a mechanism and vulnerability of ERG function; 3) characterize the pseudo-basal state in human PCa. Impact: Success of this work will 1) advance mechanistic understanding, 2) identify novel vulnerabilities of ERG-driven PCa, the most frequent PCa subtype, and 3) provide tools and approaches with wide applicability to studying lineage fate choices in cancer. This work will be performed under the collaborative and resourceful research environment at MSKCC. I have recently developed CRISPR editing tools for rapid PCa modeling (Proc Natl Acad Sci), which will be critical to advance the proposed work. My long-term career goal is to establish an independent research team that focuses on mechanistic understanding of PCa to develop novel therapeutic strategies. I have developed a detailed career plan to obtain skills in leadership, management, mentoring, grant writing, and scientific communications. I will work under the mentorship of Dr. Charles Sawyers, a leader in PCa research with a stellar track record of trainees that went on to faculty positions. In addition, I have assembled an Advisory Committee that will collaborate with me and offer training on science and career development, including Drs. Michael Shen (prostate lineage specification), Yu Chen (ERG biology), Gary Perdew (AHR biology), Anuradha Gopalan (patient sample assessment), and Christina Leslie (computational biology). My research and career development plan, together with my mentor, advisors and the exceptional academic environment at MSKCC will provide a solid foundation for my independence in translational prostate cancer research.

PROJECT NARRATIVE The ERG oncoprotein is responsible for half cases of prostate cancer, the most frequent cancer and the second leading cause of cancer death among American men. Prostate cancer features a luminal cell identity which is effectively targeted by hormone therapy, but resistance invariably occurs, thus demanding a deeper understanding of the biology underlying the cancer cell identity. This proposal seeks to elucidate the mechanisms and vulnerabilities of ERG-driven luminal cell identity during prostate cancer formation, the completion of which may reveal new treatment paradigms.