Targeting the plastic nature of prostate cancer metastasis to improve therapeutic strategies for advanced disease.
Abstract
Prostate cancer (PCa) is the most common male cancer, affecting one in seven men during their lifetime. As long as cancer is confined to the prostate, it is treatable by surgery and/or radiation therapy. The mainstay therapy for advanced PCa is androgen-targeted therapy, which starves PCa cells of hormonal androgens that are required for the cells to survive and grow. While this therapy is initially effective, some PCa cells change their physical characteristics to adapt to low levels of androgens, allowing them to survive and grow in the absence of androgens. This type of PCa, known as castration-resistant PCa, is a particularly aggressive variant and results in the cancer spreading. Because of this, it responds poorly to chemotherapy, and patients with castration-resistant disease have a very poor prognosis. Despite the recent development of new drugs that prolong the survival time of patients with advanced PCa, all patients will eventually become ill again due to therapy resistance. We have developed PCa cell models in which we can change their physical characteristics so the cells become aggressive and capable of spreading, similar to how cancer spreads in patients. This process is called epithelial to mesenchymal transition (EMT) and is bi-directional, meaning that cells that have undergone EMT can then reverse back through a process termed mesenchymal to epithelial reverting transition (MErT). EMT has been shown to make cells more invasive and resistant to therapies, and MErT is thought to allow cancer cells to start growing again once they spread to other vital organs. Our PCa models can recreate these transitions, and by capturing the cells at EMT and MErT states, we have been able to characterize the subcellular processes that underpin and control how these cells transition between the two states. Our data indicate the primary tumors of patients that express genes associated with these transitions have worse outcomes than patients that do not. More specifically, we have found that, when cells undergo EMT followed by a MErT, they do not quite revert back to their original status and express a different subset of genes. Importantly, we have shown that this gene set is expressed more highly in the secondary cancers of treatment-resistant patients compared to the primary cancer. Our study is one of few that directly supports the role of these transitions in cancer aggression and spread. We now aim to answer the following questions: “How are these post-EMT/MErT cancerous cells important to the biology of advanced PCa?” and “Can we find weaknesses that can be exploited in order to develop better-targeted therapies for patients with advanced PCa?” We aim to address these questions with the following aims: Aim 1. We will first examine whether post-EMT/MErT cells grow faster, are more resistant to current therapies, and are more invasive compared to pre-EMT/MErT cells. Aim 2. We have evidence that post-EMT/MErT cells have a different metabolism than pre-EMT/MErT cells, so we will investigate these metabolic differences further to identify pathways that we can inhibit to eliminate post-EMT/MErT cells. Aim 3. We will block each one of the genes that are unique to post-EMT/MErT cells to identify those that are important to their survival. These aims will help us better understand the biology of these cancerous cells and discover specific molecules that we can target to kill them, with the overall goal of developing more effective therapies for patients that have advanced therapy resistant PCa. This project addresses the FY19 overarching challenge of defining the biology of lethal PCa to reduce death with implications in developing treatments that improve outcomes for men with lethal PCa. My career goal is to become an independent PI and lead research that will provide advanced PCa patients with new effective therapies to extend their life. As cancer spread is the main cause of death in these
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010050
Entities
People
- Nataly Stylianou
Organizations
- Queensland University of Technology
- United States Army