The tumor microenvironment in cholangiocarcinoma - factors and phenotypes

• Applicant: Privatdozentin Dr. Anna Lena Saborowski
• Subject Area: Gastroenterology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493345156

Cholangiocarcinoma (CCA) is an aggressive malignancy with a 5-year survival below 10%. A frequent histological hallmark of CCA is the abundant tumor reactive stroma that surrounds the cancer cells. This tumor stroma is composed of cellular constituents including immune cells and myofibroblasts, structural elements such as blood- and lymphatic vessels, as well as extracellular matrix. Active recruitment of stromal cells to the site of malignant transformation results in the generation of a highly dynamic matrix that is shaped by an intricate reciprocal exchange of signals between the tumor- and the stroma cells. Although several cell types and secreted proteins have been shown to influence the development and composition or the tumor reactive stroma, the exact molecular mechanisms that induce or modulate the stroma and its cellular composition are insufficiently understood. In recent years, with the introduction of immune-oncology (IO) into daily oncological practice, cells of the tumor microenvironment (TME) shifted into the focus of anti-cancer therapies. Thus far, biliary tract cancers demonstrated only minor sensitivity to IO, and, with the exception of microsatellite instability, predictive biomarkers are lacking.Regarding the prevailing need for improved therapeutic approaches in CCA, paired with an uncertainty concerning potential benefits and risks of targeting the tumor stroma, a deeper understanding of the TME dynamics appears mandatory.In this project, we employ two independent, but complementary approaches towards the characterization of the TME in intrahepatic CCA. In work package 1 we will use established murine in vivo models, as well as organoids and tumor-derived cell lines in order to characterize specific stromal modulators and genetic factors that we identified in our previous work with a focus on their functional implications on tumor- and tumor stroma development. In work package 2, we will adopt a comprehensive approach to annotate and classify the TME in human intrahepatic CCA. We have compiled clinical and molecular information on a retrospective cohort encompassing over 160 patients and further complemented this dataset with multispectral imaging analysis that not only allows for the simultaneous quantification of multiple immune cells on a single slide, but also provides information on their spatial relationships in the different tumor compartments (e.g. tumor center vs. - margin). Starting with a “global” assessment of gene expression data, we will gradually “zoom in” and dissect the reciprocal cellular interactions using automated image analysis and spatial transcriptomics.We expect that this project will aid in the identification of vulnerabilities that can be therapeutically “hijacked” to optimize existing treatments. Furthermore, we believe that a TME-centered CCA classification will improve patient stratification and help to allocate patients to the most suitable treatment modalities.

• DFG Programme: Research Grants