Cancer metastasis accounts for 90% of cancer related deaths. Presence of tumor cells in the lymph nodes indicates poor patient survival and tumor spread that eludes current therapies. The factors that control the spread of tumor cells via the lymphatic system to lymph nodes and other organs such as the liver and lungs is not very well understood and remains a hurdle to the development of targeted clinical interventions for many types of cancers. Cancer of the liver has a high incidence in Texas. In fact, cholangiocarcinoma (CCA) is an aggressive cancer of the liver bile ducts that is increasing in incidence in Texas. CCA is often detected at late stages limiting surgical options leaving pat...

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Cancer metastasis accounts for 90% of cancer related deaths. Presence of tumor cells in the lymph nodes indicates poor patient survival and tumor spread that eludes current therapies. The factors that control the spread of tumor cells via the lymphatic system to lymph nodes and other organs such as the liver and lungs is not very well understood and remains a hurdle to the development of targeted clinical interventions for many types of cancers. Cancer of the liver has a high incidence in Texas. In fact, cholangiocarcinoma (CCA) is an aggressive cancer of the liver bile ducts that is increasing in incidence in Texas. CCA is often detected at late stages limiting surgical options leaving patients to face the disease with limited therapies. The goal of this proposal will be to understand the mechanisms that regulated the communication between the tumor and lymphatic vessel cells that guide tumor cell entry into the lymphatic vessels and aids cancer spread. Previous studies have shown that increased levels of bile acids (produced by the liver) are detected in the blood of CCA patients and accumulate in lymph nodes near the tumor. Our study will determine whether these increased bile acid levels promote CCA-lymphatic communication and aids metastasis and CCA tumor progression through lymphatics. The proposed study will examine the use of specific FDA approved and pharmacological inhibitors to inhibit the bile acid mediated signaling that promotes tumor growth and subsequent spread through lymphatics in several models of CCA. We will also identify the specific molecular profile of metastatic lymph nodes to enable targeted interventions. Successful completion of this study will provide insight into the mechanisms by which CCA progresses leading to dissemination to lymph nodes and will provide novel insights enabling development of targeted clinical interventions for CCA and potentially other solid tumors.

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