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

NF-κB信号通路是炎症和肿瘤的媒人。有许多研究表明其在胰腺癌中的重要性，重点是在上游调节该途径的激酶和受体。尽管这些蛋白对NF-κB的功能非常重要，但它们在其他信号通路中具有多效性影响。为了绕过这一问题，一种方法是将重点放在下游转录因子的基础科学认识和治疗开发上。我们之前的研究已经表明了NF-κB转录因子RelA和RelB在胰腺癌的发生和持续性中是如何以及为什么重要的。迄今为止，c-Rel已在血液恶性肿瘤中进行了分析。与RelA和RelB不同的是，关于c-Rel在实体瘤中的功能的研究非常有限。我们认为，这些研究的缺乏不是由于c-Rel在这些实体中的作用微不足道，而是无意识的忽视。因此，在本提案中，我们总结了许多先前的研究表明c-Rel在实体瘤中的作用。重要的是，我们提供的数据预示着c-Rel在胰腺癌中的重要功能。特别是，我们提供了初步证据，证明在基础研究中探索c-Rel功能将为开发治疗方案铺平道路。通过使用不同的胰腺癌小鼠模型，我们提供了Rel基因过表达如何降低总生存率的证据。基于我们的小鼠移植实验，我们也获得了c-Rel过表达上调转移的证据。通过使用其他小鼠模型，我们旨在阐明c-Rel功能在原发性肿瘤发生和转移中的重要性。其中，我们已经开始培育的Rel条件敲除小鼠模型将具有特别重要的意义。同时，我们的目标是进行体内和体外实验，分析c-Rel在功能和分子上的影响。因此，我们已经与多个团队建立了协作网络，这些团队都是各自领域的专家。总体而言，在本提案中，我们提供了工作方案，其中我们将描述以下假设“NF-κB转录因子c-Rel调节胰腺癌的严重程度和转移潜力”。最终，通过使用先前发表的c-Rel抑制剂，我们的目标是制定降低原发性肿瘤严重程度和转移性负担的策略。

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.