Role of the Tumor Neuroenvironment in Prostate Cancer Metastasis
Abstract
A major obstacle to curing lethal prostate cancer is the lack of understanding for how prostate cancer cells interact with other cells in organs like the lung and liver to form lethal disease. Previous research in mice demonstrates that nerves promote growth of the primary prostate tumor. However, how these nerves interact with prostate cancer cells in organs like the lung and liver to cause lethal disease has not been determined. We developed a genetically engineered mouse prostate cancer model which mimics human prostate cancer in that mice develop lethal disease when prostate tumor cells travel to organs like the liver and lung and form tumors. Our mouse model is designed so that prostates lack two critical tumor suppressor genes necessary for preventing prostate cancer in both mouse and human. The tumor cells that develop also express a red fluorescent gene, so we can see these tumors when using specialized microscopes. I hypothesize that gaining an understanding for how nerves interact with prostate cancer cells in the lung and liver will help us fight lethal prostate cancer. To test my hypothesis, I propose two aims. In aim 1, I will use an imaging microscope to visualize red fluorescent tumor cells in the lung and liver taken from our prostate cancer mouse model. To visualize nerves interacting with prostate cancer cells, I will breed our prostate cancer model to another genetically engineered mouse model that expresses nerves labeled with a green fluorescent gene. The result will be a mouse that has prostate tumor cells labeled red and nerves labeled green. I will harvest the lung and liver from these mice and, using an imaging microscope, look for red tumor cells interacting with green nerves. In aim 2, I will study nerve-tumor cell interactions by culturing these cells together on a specially designed plate. This plate consists of separate compartments for growing nerves and cancer cells. Importantly, as the nerves grow, they will extend through a connecting channel into the region where tumor cells are growing and we can observe these interactions. To identify how this interaction helps tumor cells grow or move, I will use either gene editing technology to remove nerve specific genes or drugs that block nerve specific genes. This will tell me which gene is critical for nerve-tumor cell interaction. The clinical application for the knowledge gained from my research can used to design therapies to block nerve-tumor cell interactions in prostate cancer and may be used as a treatment to improve clinical outcomes, especially for patients suffering from aggressive disease. The benefits from such therapies would be to block growth of tumor cells that have spread to the liver and lung with the ultimate goal of my findings to improve patient survival. The projected timeline to achieve a patient-related outcome from my findings depends on whether the gene(s) I identify as critical for nerve-tumor cell interaction in prostate cancer can be targeted with an existing repurposed drug. Rigorous preclinical testing of therapies in mice will be critical for avoiding risks of causing toxicity. I believe this research project will provide the opportunity for me to learn about the exciting area of nerve cancer biology. I will develop new technical skills including learning gene editing and imaging technology and will collaborate with and learn from experts in neuroscience and cancer biology. I will also develop public speaking and leadership skills through scientific presentations and mentoring students. I will receive excellent scientific guidance and career development from my mentor, Dr. Lloyd C. Trotman, an innovative leader in prostate cancer research and mouse modeling. He is well-published and has successfully trained postdoctoral fellows now leading independent careers as academic faculty. Overall, I am confident that my research, which addresses the Overarching Challenge of defining the biology of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210358
Entities
People
- Mary Doherty
Organizations
- Cold Spring Harbor Laboratory
- United States Army