Developing Functional Human Cell Models to Study Initiation and Progression of Prostate Cancer between AA and EA men

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Project Summary Prostate cancer (PCa) is the most frequently diagnosed male cancer and the second leading cause of cancer deaths in men in the United States. This growing public health challenge is aggravated by disparities in the incidence and mortality of PCa between African-American (AA) and European-American (EA) men. For example, the incidence of PCa is almost 60% higher in AA men and the mortality rate 2-3 times greater. While access to medical care may contribute to these differences, other studies suggest that cell-based differences may play a critical role. Unfortunately, no primary human prostate cell cultures are available for interrogating potential cellular alterations during early carcinogenesis. Organoid culture models work well for growing normal prostate cells and advanced PCa, but fail to succeed with primary PCa. CR (Conditional Reprogramming) culture, which was developed by Dr. Liu (PI) and his colleagues, is changing the landscape for generating in vitro human cancer models. CR technology allows to establish cell cultures from normal prostate, primary PCa and advanced PCa. CR cells from normal epithelium can fully differentiate when placed in conditions that mimic their natural environment, while CR cells from a primary prostate tumor exhibit an abnormal karyotype and form tumors in SCID mice. In the current application, in an effort to define the biological basis for their clinical disparities, we first propose to probe primary AA and EA normal prostate cells for differences in their susceptibility to immortalization and transformation. Then, we will determine response of biobanked normal and tumor CR cells to testosterone from AA and EA patients in presence or absence of their corresponding fibroblasts. Then, we will compare the genetic and biological properties of tumor CR cultures from AA and EA patients, including migration/invasion, anchorage-independent growth, tumor formation in presence or absence of their corresponding fibroblasts. Finally, we will compare genetically, epigenetically and phenotypically CR cells from AA and EA patients with metastatic and castration resistant PCa. Upon completion of this application, we will have established a living biobank with novel functional cell models, including matched normal and tumor prostate CR cells and their corresponding fibroblasts from AA and EA patients, immortalized AA and EA prostate cell lines and transformed AA and EA cell lines with annotated genomic and patient’s clinical information. These novel models include prostate cells at normal, primary PCa and advanced PCa and will provide an invaluable and novel resource for studies of initiation and progression and health disparity studies of PCa.