Dissecting the function of c-Rel in pancreatic cancer and its therapeutic implications

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NF-κB signaling pathway is the matchmaker of inflammation and cancer. There are many studies signifying its importance in pancreatic cancer, with a focus on the kinases and receptors regulating the pathway at the upstream. Although these proteins are functionally very important for NF-κB function, they have pleiotropic impact in other signaling pathways. In order to bypass such a problem, an approach is to rather focus on downstream transcription factors for both basic science percipience and therapeutic exploitation. Our previous research already showed how and why the individual NF-κB transcription factors RelA and RelB are important in pancreatic carcinogenesis and persistency. c-Rel has so far been analyzed in hematological malignancies. Unlike RelA and RelB, there are only limited amount of studies regarding c-Rel function in solid tumors. We believe that lack of these studies is not due to the insignificant function of c-Rel in these entities but rather an unconscious overlook. Therefore in the present proposal, we summarized many previous studies signifying the role of c-Rel in solid tumors. Importantly, we offer data portending the noteworthy function of c-Rel in pancreatic cancer. Particularly, we provide preliminary evidence how exploration of c-Rel function in basic research would pave a way for the exploitation of therapeutic options.With the use of different pancreatic cancer mouse models, we provide evidence how Rel genetic overexpression reduced overall survival. Based on our mouse transplantation experiments, we also procure evidence that overexpression of c-Rel upregulated metastasis. With the use of additional mouse models, we aim to elaborate the importance of c-Rel function in primary tumor carcinogenesis and metastasis. Among these, the Rel conditional knock-out mouse model will be of special importance which we already started to breed. In parallel, we aim to perform both in vivo and in vitro experiments analyzing c-Rel impact both functionally and molecularly. Accordingly, we already generated a collaboration network with multiple groups which are all experts in their respective fields.Overall, within this proposal we provide the work programme in which we will delineate the following hypothesis “NF-κB transcription factor c-Rel regulates the severity and metastatic potential of pancreatic cancer”. Eventually, with the use of previously published c-Rel inhibitors, we aim to develop strategies reducing both primary tumor severity and metastatic burden.