HUEBER

The effectiveness of current cancer therapies is limited by tumor resistance to chemotherapy and targeted therapies. Combinatorial multi-pathway targeted therapies and the use of predictive biomarkers to stratify patients who may benefit from therapies are key strategies to overcome this therapeutic challenge. They require identification of molecular targets and biomarkers and thus the understanding of molecular basis of signaling pathways that can be targeted in order to reconstitute programmed cell death (apoptosis) and prevent uncontrolled proliferation of cancer cells. In this context, understanding the molecular basis of the imbalance between cell death and cell survival acquired by cancer cells might lead to more efficient and targeted anti-cancer therapy and represents the main goal of our team. Amongst the proteins able to regulate both survival and death functions of the cells are the members of the TNF receptor (TNFR) superfamily.

The multi-modal signaling in many cancer cell types, including colon, breast, and glioblastoma, has been demonstrated for the prototype of the TNFR superfamily, the receptor Fas (TNFRSF6/CD95/APO-1), so far considered a “purely” pro-apoptotic receptor. As Fas activates both cell death and survival, it is a good candidate for targeted therapies promoting or preventing cancer depending on cellular context. Our main recent research accomplishments concern the description of Fas multi-signaling regulation in cancer and its application in cancer therapy. Our work significantly contributed to a clearer understanding of how the Fas signaling is shifted from tumor-suppressing to tumor-driving mode, as well as presented the means to appropriately take control of the duality of Fas signaling in different pathological contexts in order to increase therapeutic success. In continuation of our research interest, we aim to achieve a deeper understanding in the versatility of Fas signaling and to clinically apply the knowledge in colorectal cancer (CRC) therapy. We will dissect the control of Fas signaling in the level of protein modifications, membrane receptor crosstalk, and multi-cellular regulation with the main aim to address the outstanding questions in the field of TNF receptor signaling and cancer cell biology: How does Fas multi-signaling influence CRC cellular functions and behavior and the CRC progression? And how can we use this information to the benefit of anti-cancer therapy?