Resolving and Translating Communication Within the Prostate Cancer Microenvironment
Abstract
Prostate cancer (PC) remains a major cause of cancer-related death. While the vast majority of research on PC has focused on cancer cells themselves, it is now evident that the cells that surround the tumor (i.e., the PC’s supporting surroundings, termed the tumor microenvironment) are very important. The tumor microenvironment includes specialized cells termed fibroblasts that communicate with the cancer cells and promote cancer progression, but the nature of this “conversation” is poorly-defined. In order to understand the communication signals between cancer cells and surrounding fibroblasts in the tumor microenvironment, we have used an experimental technique called mass spectrometry (MS)-based proteomics. This technique allows us to identify, in an unbiased fashion, key proteins that allow cells within a tumor to communicate with each other. These proteins differ in the cancer microenvironment compared to normal tissue. Our preliminary studies have revealed an increase in the signaling (“conversational”) pathway involving a protein termed lysyl oxidase-like 2 (LOXL2), which connects cancer cells to the surrounding tissues and cells. Furthermore, we have determined that cancer-associated fibroblasts produce LOXL2, causing the surrounding tissue to change and allow cancer cells to move around more easily, likely leading to metastasis. Since targeted drugs against LOXL2 are currently undergoing Phase I/II testing, these findings provide “proof of principle” that our strategy can lead to new anti-cancer therapies. In addition, we have established a powerful new technique, termed CTAP, that allows us to make a detailed transcript of the conversation between the two types of cells (i.e., PC cells and surrounding fibroblasts) in a level of detail never seen before. By understanding how cancer cells and their environment talk to each other, we can develop new drug targets to kill cancer cells. Therefore, the overall aim of this proposal is to identify signaling pathways between cancer-associated fibroblasts and normal prostate or PC cells that can be targeted to improve management of PC. The specific aims encompass characterization of the role of the LOXL2 signaling axis in the development and progression of PC and identification of additional signaling pathways that mediate communication between cancer cells and their surroundings. We will define which communication mechanisms are best targeted by tailored drugs. Furthermore, using patient cancer tissue, we will build on this work to identify potential biomarkers of PC initiation, progression, and death. The outcomes of this research program will be to determine whether LOXL2 and additional pathways of intercellular communication represent therapeutic targets for blocking PC development or the metastatic spread of high-risk localized PC and to identify potential biomarkers of prostate carcinogenesis or patient prognosis. The latter can be used to identify patients with high-risk localized disease that requires appropriate treatment. By identifying novel drug targets for blocking metastatic spread of high-risk localized PC and characterizing prognostic biomarkers that help identify patients that are at highest risk of developing metastatic disease and require appropriate therapy, this work will impact the two PCRP Challenges, “Define the biology of lethal prostate cancer to reduce death,” and “Develop treatments that improve outcomes for men with lethal prostate cancer.” In the short term (3 years), this project will already have made significant impact by providing important biological insights into the communication between PC cells and the tumor microenvironment, the identification of novel therapeutic targets, and providing proof of principle that the tumor microenvironment can be targeted for drug treatment. This would be a highly influential development that would drive an intensive research effort by other investigators to determine other pot
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910671
Entities
People
- Roger J. Daly
Organizations
- Monash University
- United States Army