Notch3 as a regulator of cancer-associated fibroblast reprogramming and functions in intestinal cancer
Worldwide Cancer Research
Alexander Fleming Biomedical Sciences Research Center
The Notch signaling pathway plays an important role in development, homeostasis, and disease, such as cancer, where its therapeutic potential is under consideration. However, the role of individual receptors, their cell-specific functions, and their implication in cancer therapy is not yet fully understood. Notch3 is of particular interest, as it is overexpressed in colorectal cancer (CRC) and associated with worst prognosis. Our preliminary data suggest that in patients and animal models of CRC, Notch3 is predominantly expressed in cancer-associated fibroblasts (CAFs) and more specifically in intratumoral perivascular fibroblasts. However, the mechanisms driving Notch3 activation in fibroblasts and its role as a regulator of CAF reprogramming and downstream functions are not known. In this proposal, we bring forward the hypothesis that endothelial-specific Notch ligands can activate Notch3 signaling in adjacent perivascular fibroblasts, leading to their activation and downstream functions associated with either or both angiogenesis and cancer cell proliferation, ultimately leading to tumor growth. Notch3 inhibition could thus have a therapeutic effect either alone or in combination with standard therapy. To address this hypothesis, we will combine in vitro and in vivo genetic targeting, 2D and 3D cell co-culture techniques, high-throughput single-cell, and bulk RNA sequencing, and mouse models of disease. We expect that this study could lead to a better understanding of the role of fibroblast-specific Notch3 in CRC and the potential of its inhibition in the clinic. In addition, it will provide further insight into the mechanisms driving CAF reprogramming and functions and thus help identify novel targets for therapeutic approaches, as well as diagnosis and patient stratification.
2.1 Biological and endogenous factors