Multiplex functional interrogation of combinations of genetic alterations in prostate cancer
Abstract
Prostate cancer is the second leading cause of cancer-related death in men in the United States. The initiation of cancer is a multi-step process where normal cells acquire mutations in genes. Ultimately, these genetic abnormalities lead to the unchecked growth of cells that form cancer. Advances in sequencing the genetic code of tumors has led to the identification of significant heterogeneity in prostate cancers. This means that each cancer may arise from a different set and sequence of gene mutations. This information speaks to the complexity of cancer in general and partly explains why each man faces a different outcome related to their prostate cancer. Wrangling this genetic complexity is necessary to understanding prostate cancer biology, resistance to therapies, and developing next-generation approaches to treat the disease. In this proposal, we aim to develop an innovative and powerful approach to systematically study the diverse combinations of genetic events in prostate cancer that contribute to the heterogeneous nature of the disease. In this proposal, we will take advantage of new technologies that enable the growth and monitoring of benign prostate cells in a three-dimensional system called organoid culture. Prostate cells grown in organoid culture form structures that have an appearance and architecture akin to normal glands (prostate organoids) found in normal prostate tissue. We have found that prostate cells can be manipulated and genetic factors may be readily introduced to understand the effects of these factors on cell growth, organoid appearance, and initiation of prostate cancer. We will marry this approach with high-throughput bulk and single-cell sequencing technologies to develop a powerful platform to address important questions related to prostate cancer biology. In this proposal, we will identify how specific genetic factors associated with cancer may have different effects, depending on the tissue context from which they arose; understand the cooperation of multiple factors to promote prostate cancer formation; and understand how the sequence in which genetic factors are introduced affect prostate cancer development. I am uniquely poised to complete these studies because my laboratory and I have established the feasibility of the techniques required for this proposal. This project will lead to the identification of diverse combinations of genetic mutations that give rise to prostate cancer, as well as provide a better understanding of how this impacts prostate cancer heterogeneity and therapeutic response. The outcomes of these studies will ultimately benefit the prostate cancer research community and aid in the development of personalized approaches to improve the treatment of men with prostate cancer. My goal is to use the knowledge and skills gained from this proposal to be a successful prostate cancer scientist with an independent, academic research program focused on understanding cancer initiation/progression and translating these findings to new therapeutic approaches for patients. This proposal will further my career goal in several important ways: (1) obtaining fundamental knowledge and cutting-edge laboratory skills related to prostate cancer research; (2) establishing collaborations with investigators with diverse expertise and interest in prostate cancer; (3) enhancing my communication skills and mentoring skills, which are beneficial to my growth and achievement of my long-term career goal to be an impactful, independent investigator in the field of prostate cancer research. I am currently mentored by Dr. John Lee, M.D, Ph.D., who is a creative young investigator with expertise in aggressive prostate cancer. Dr. Lee will monitor my research progress with scientific rigor and help me build the scientific and professional skills that are necessary to become an independent investigator. In addition, I will also benefit greatly from interactions with my co-mento
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010083
Entities
People
- Shan Li
Organizations
- Fred Hutchinson Cancer Center
- United States Army