Targeting Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma

• Applicant: Dr. Sven Loosen
• Subject Area: Gastroenterology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421060763

Cholangiocarcinoma (CCA) represents the most common biliary tract malignancy and is associated with a dismal prognosis, which is mainly due to a high rate of chemoresistance and the lack of specific and targeted therapeutic approaches. Moreover, the diversity or risk factors makes it difficult to establish reasonable prevention strategies, which resulted in an increasing CCA incidence rate over the last decades and corroborates the vital need for a better understanding of the underlying pathobiology to develop novel therapeutic strategies.The tumor microenvironment (TME) has recently become of increasing interest to the field of liver cancer research. Cancer-associated fibroblasts (CAF), which represent a dominant cell type in the TME of solid tumors, were shown to play a crucial role in cancer proliferation, resistance to cell death, invasiveness as well as metastasis. Intrahepatic CCA (ICC) represents a highly desmoplastic tumor with abundant αSMA-positive CAF and both clinical and in vitro studies have suggested a tumor-promoting role of CAF in ICC. Nevertheless, functional in vivo data that delineate the exact function of CAF in the context of CCA are missing. The current research proposal aims at investigating the specific role of CAF in the context of ICC at the Department of Medicine at Columbia University Medical Center under the supervision of Prof. Dr. Robert Schwabe, who is an internationally recognized expert in the field of experimental hepatology, hepatic stellate cell biology and hepatocarcinogenesis. During my two-year postdoc, I first seek to dissect the specific function of CAF on ICC development and survival by genetically ablating or inhibiting CAF in vivo and investigating the underlying cellular mechanisms, including tumor cell proliferation and cell death, activation of pro-proliferative and anti-apoptotic pathways, gene expression of pure tumor cells and the TME as well as the TME composition by single-cell RNA sequencing and FACS. In a second step, I aim at understanding the specific mechanisms and underlying pathways by which ICC triggers CAF recruitment, proliferation and activation in order to achieve the long-term goal of therapeutically disrupting the tumor-promoting ICC-CAF crosstalk. Finally, I intend to identify specific pathways through which CAF stimulate ICC growth based on the hypothesis that CAF promote ICC tumor growth mainly via the extracellular matrix (ECM) and that ECM-mediated stiffness and the subsequent activation of mechanosensitive signaling of ICC tumor cells represent key drivers of ICC tumor promotion. In summary, my research proposal will apply innovative genetic approaches for CAF and tumor manipulation in combination with state-of-the-art single-cell sequencing, mechanobiology as well as the analysis of human CCA samples to elucidate mechanisms and consequences of the ICC-CAF crosstalk, which could provide a basis for future therapeutic strategies for this devastating type of cancer.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Robert F. Schwabe