Defining the Effects of the Liver Microenvironment on Metastatic Colon Cancer
Abstract
Title: Defining the Effects of the Liver Microenvironment on Metastatic Colon Cancer Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Area: Colorectal Cancer Colon cancer causes a high burden of disease in Veterans, and survival rates for metastatic colon cancer are low. Although metastatic disease is responsible for the vast majority of colon cancer deaths, we know very little about how colon cancer cells that have broken off from the primary tumor in the colon and are growing as a metastasis in the liver are different from the colon cancer cells in a primary tumor. The main focus of this proposal is to examine how growth in the liver alters the behavior of colon cancer cells, with the ultimate goal of identifying specific weaknesses that the cancer cells have when they are growing the liver, potentially allowing for treatment approaches that specifically target metastatic colon cancer. Additionally, we will collaborate with Dr. Sangeeta Bhatia’s lab to test whether we can specifically detect metastatic colon cancer using state-of-the-art nanosensors that they have developed. This project aims to bridge basic science and translational approaches, with the following end-goals: 1. Identifying specific vulnerabilities that colon cancer cells have when they are growing as metastases in the liver, such that therapies tailored to treating metastatic colon cancer can be developed. 2. Developing new sensors for early diagnosis of metastatic colon cancer. The earlier metastatic disease is detected, the better the prognosis, so any improvements in early detection will provide a large benefit to Veterans with colon cancer. To accomplish the first goal, we will utilize cutting edge “organoid” models (i.e., 3-D cancer models) of colon cancer, which our lab has pioneered, to carefully compare metastatic and non-metastatic cancer cells. We will use multiple techniques to compare how the cancer cells that have grown as a liver metastasis are different from the cells that have not metastasized. This approach will include identifying gene networks and signaling pathways that differ between metastatic vs. non-metastatic cancer cells, testing how they respond to chemotherapy, and identifying factors that differentially promote the growth of metastatic cancer cells compared to their non-metastatic counterparts. We hope to ascertain specific strengths and weaknesses that the colon cancer cells acquire when they grow in the liver, ultimately allowing for the development of tailored therapies to better treat metastatic disease. Preliminary work done in collaboration between the Yilmaz and Bhatia labs has already identified one such difference between metastatic and non-metastatic cancer cells. We have found that specific sets of enzymes used by cells to digest the material that surrounds them are highly elevated in the colon cancer cells, specifically when they grow in the liver. The Bhatia lab has developed nanosensors which specifically detect the activity of the enzymes which we observed to be highly elevated in the liver metastases. So we aim to test whether this liver metastasis specific signature can be used for early detection of metastatic colon cancer. Military Relevance: Colorectal cancer is the third most common cancer among US Veterans, and ionizing radiation is a military-related exposure risk factor, which leads to elevated risk of colorectal cancer. The experiments outlined in this proposal will help us understand the biology of colon cancer and advance our understanding of metastatic disease in particular, which is the primary driver of colon cancer deaths. Furthermore, our work will help to address gaps in early detection of metastatic colon cancer. We will collaborate with the Bhatia lab to determine whether the metastatic protease signature we have identified can be used for early non-invasive detection of metastatic colon cancer, which is an urgent medical need for Veterans
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010661
Entities
People
- Omer Yilmaz
Organizations
- Massachusetts Institute of Technology
- United States Army