Novel targeting mechanisms for alcohol-enhanced liver metastasis of colorectal cancer

About This Grant

This is a new multiple-PI R01 application to test the innovative approach of targeting hepatic cell signaling mechanisms involved in alcohol-related colorectal liver metastasis (CRLM). The aberrant use of alcohol associates with the development of cancers including colorectal cancer (CRC), the second leading cause of death in the United States. Most CRC deaths are due to metastases to the liver, the foremost site of secondary organ involvement. Despite advancements in screening and treatments for primary CRC, few effective options are available for liver metastatic disease. In search of targetable mechanisms involved in CRLM, research has shown a correlation between the expression of the tumor antigen, carcinoembryonic antigen (CEA), and poor outcomes of CRC, especially in patients with an alcohol use history. CEA is overexpressed in metastatic CRC cells and stimulates macrophages in the host liver to produce inflammatory factors that promote CRLM. CEA signaling in alcohol-affected MΦs leads to the production of metastatic factors and the activation of hepatic stellate cells (HSC) resulting in matrix remodeling for CRC cell expansion in the liver. We hypothesize that pre- existing alcohol-associated liver disease drives hepatic macrophages toward a CEA-responsive, prometastatic phenotype that can be targeted by novel nanoparticle (NP) formulations. To investigate this, three specific aims are proposed to 1) develop and optimize novel NPs for maximal inhibition of alcohol-related macrophage activation by CEA, signaling via miR-155, and HSC transformation via inhibition of the chemokine receptor CXCR4; 2) characterize the effectiveness of the anti-CRLM NPs and the contribution of metastasis-promoting MΦs using ex vivo and in vivo assessments; and 3) to perform transcriptomic analysis to determine the intrahepatic MΦ gene signature, localization, and prometastatic properties during alcohol-associated CRLM. The successful completion of this work will define the effectiveness of novel therapeutic strategies aimed at reducing or eliminating CRC metastatic burden in the liver. Also, we will determine hepatic cell involvement during alcohol-mediated exacerbation of CEA signaling and advancement of CRLM and underlying mechanisms of action of anti-CRLM nanoparticles. This is a clinically relevant topic and priority area of investigation which has the potential to significantly impact the clinical care for individuals with liver metastasis of colorectal cancer. Overall, this characterization of targetable macrophage populations and tumor-promoting signaling pathways can lead to translational breakthroughs in the field, and next-step evaluations to effectively reduce the severity of metastatic disease.