While approximately 50% of prostate cancer patients present with disseminated tumor cells, only 1% of those disseminated tumor cells will ultimately progress to macrometastatic lesions, with the rest either dying or remaining dormant. The complex interactions between the multiple cell types in the bone-marrow microenvironment both influence and are influenced by tumor cells present in the hematopoietic stem cell niche. What cues the bone-marrow microenvironment provides such that DTCs either maintain their dormancy or proceed to proliferate are of paramount importance to the study of prostate cancer progression and therapeutic resistance. The study of why tumor cells enter into, or escape from, dormancy, however, are limited by shortcomings in current in vivo and in vitro systems. The application of DNA-directed single cell patterning to pattern six cell types in a fabricated in vitro bone-marrow niche will enable me to study the role of the microenvironment in tumor progression at a common secondary location in prostate cancer. This intricate system will allow me to specifically interrogate the contributions of different phenotypes to disease outcomes through the following specific aims: 1) To fabricate and validate an in vitro bone-marrow niche. 2) To incorporate and monitor cells from established prostate cancer cell lines in a highly interactive in vitro bone-marrow microenvironment. 3) To investigate the relationship between cancer stem cell and epithelial-mesenchymal transition phenotypes and tumor cell dormancy. Following optimization of cell culture and patterning parameters, I will use high-throughput photolithography- based DNA-directed cell patterning to incorporate osteoblasts, osteoclasts, osteocytes, vascular cells, macrophages, and tumor cells into arrays of microenvironments for the systematic study of key parameters. In particular, I will study the influence of different cell types on both the bulk tumor cell population and tumor cells pre-sorted for specific stemness and/or epithelial-mesenchymal transition phenotypes. These studies will initialize a new tool in the study of tumor cell dormancy as well as take the first steps toward its application to the systematic and replicable study of factors affecting tumor cells in the microenvironment. This specifically addresses a problem in prostate cancer, but can ultimately be generalized to other cancers that localize to the bone marrow or other tumor microenvironments. The work in this proposal will be conducted at the University of California, Berkeley, under the sponsorship of Professor Lydia Sohn. In addition to conducting the aforementioned research, I will pursue responsible conduct in research and professional development training over the course of the fellowship tenure. I will also communicate my results and gain professional experience by attending conferences that highlight research in the fields of cancer biology and the biomedical sciences. My postdoctoral experience will allow me to gain skills and experience to prepare me for my long-term career goal of tenure-track academic faculty.
One in nine men in the United States will be diagnosed with prostate cancer in his lifetime, and the ability to discern which tumors will proceed to macrometastatic lesions can guide clinical decision making. This research has long-term implications both in guiding treatment selection and in the identification of future therapeutic targets for late stage disease. By elucidating the interactions within the microenvironment that promote disease progression, this research will contribute to fundamental knowledge of prostate cancer and enable the optimization of disease management.
