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Targeting the Reactive Stroma-Tumor Cell Interplay in CCA
Mario Strazzabosco MD, PhD, MSc
Liver Center and Yale Cancer Center, Department of Medicine, Yale University, New Haven, CT.
The lecture will present a discussion of the tumor microenvironment in cholangiocarcinoma. This is a strikingly heterogeneous and diversified ecosystem generated by signals originating from the cancer cells and that rests on a wide array of factors that enables an intense communication between cell types. The signals exchanges include cyto- and chemokines, growth factors including PDGFs, TGFβ, VEGFs, as well as morphogenetic signaling. These signals are coordinated and amplified by a group pf mesenchymal cells called cancer associated fibroblasts (CAF). These are activated myofibroblasts, originating from hepatic stellate cells and/or portal fibroblasts. Recent data obtained though single cells transcriptomics has identified different clusters of CAF in CCA; each of them with specific putative function. Several other cell types populate the tumor stroma, including tumor associated neutrophils and macrophages, T-cells, lymphatics, and endothelial cells. Among different CCAs there are substantial variations in the composition of the tumor microenvironment, and this may have an important impact on CCA invasiveness and response to treatment, CCAs characterized by more intense CAF or lymphocyte infiltration showing different prognosis or response to therapy. Furthrmore, VEGF-C secreted by CAF attracts the lymphatic endothelium and facilitates the migration of CCA cells into the lymphatic vessels. In CCA also the extracellular matrix undergoes significant changes, and represent a potential target for treatment. The recent advances in immune therapy of solid cancers have increased our interest into the role of innate and adaptive immunity. This has highlighted further complexity and heterogeneity in the CCA microenvironment immune regulation and strong relationships with treatment response and prognosis. The hope is that combining the information from morphology, transcriptomics, cell biology and immunology we will be able to personalize treatments and by interfering with the tumor microenvironment, intercept CCA at an earlier stage.
Speakers
Mario Strazzabosco