Decoding and Disrupting the Coupled Cellular Plasticity and Myeloid Cell Instigation in Metastatic Prostate Cancer
Abstract
Scientific Objective and Rationale: Primary prostate tumors are almost never lethal. It is the distant metastases developed in vital organs such as lung and bone that lead to prostate cancer-related death. Therefore, toward the goal to extend lives for patients with advanced prostate cancer, it is of paramount importance to understand how metastasis happens and what to target in order to prevent, decelerate, or eliminate metastasis. Unfortunately, metastasis research has been lagging behind many other areas of cancer research primarily because it is highly complex and very difficult to model and study. Recently, there is an emerging theory to explain metastasis. In this theory, cancer cells of solid tumors morph from an epithelial status to a mesenchymal status (similar to cells of connective tissues) so that they gain the mobility required for leaving the primary organ. However, once they travel through the blood circulation to the distant organ, they need to revert from mesenchymal to epithelial morphology in order to anchor and colonize the organ and form metastases. This epithelial-to-mesenchymal transition (EMT) followed by mesenchymal-to-epithelial transition (MET) is an appealing hypothesis; however, it remains unclear whether prostate cancer displays such level of cellular plasticity and, if so, what molecular mechanism controls the process. Indeed, just describing the process is of little clinical use. Only by understanding the underlying molecular mechanisms can we identify therapeutic targets. Our research is focused on discovering the mystery behind metastasis. Recently, we developed a highly metastatic prostate cancer model in mice and derived various prostate cancer cell lines from this model that recapitulate each stage of metastasis: cells escaping the primary tumor, cells in the blood circulation, and cells successfully colonizing the lung and bone. By comparing these cells at the morphological and molecular levels, we found that prostate cancer indeed follows the EMT-MET pathway to metastasize, yet more importantly, we identified the master regulatory transcription factors (MRTFs) that control the MET step. In order for prostate cancer cells to undergo MET after arriving at the distant organ, they need to receive signals from a group of immune cells called neutrophils to activate these MRTFs. In the proposed project, we aim to first define the precise molecular mechanism to explain the function of these MRTFs and the contribution from neutrophils. Next, we will test whether metastasis can be reduced or even eradicated if the MRTFs or neutrophils are inhibited through use of RNA interference technique or pharmacological inhibitors. Specifically, we will test two very promising inhibitors: one used in the clinic to treat rheumatoid arthritis and the other used in a phase I clinical trial to treat metastatic melanoma. Therefore, if we succeed, there is a potential to repurpose these drugs to target metastatic prostate cancer. Lastly, we will use a large number of clinical samples of prostate cancer to stain MRTFs as well as markers of MET and neutrophils in order to provide clinical support for the newly discovered mechanism and potential ideas of therapeutic targeting of metastasis. Applicability of the Research: Our project addresses two of the FY19 PCRP Overarching Challenges: (1) define the biology of lethal prostate cancer to reduce death and (2) develop new treatments to improve outcomes for men with lethal prostate cancer. By finding novel mechanisms of prostate cancer metastasis, our research will illuminate new prognostic biomarkers and therapeutic targets for treating lethal prostate cancer. By testing drugs that are promising to inhibit neutrophils, we will potentially generate key preclinical evidence that these drugs could reduce the mortality of prostate cancer patients. Our research will help a highly vulnerable patient population the most, the ones who are at high ris
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010332
Entities
People
- Xin Lu
Organizations
- United States Army
- University of Notre Dame