Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer

项目摘要/摘要 胰腺导管腺癌(PDAC)是癌症相关死亡的第三大原因，并在不久的将来 在接下来的几年里成为第二个。大量的流行病学研究表明，肥胖会增加 PDAC的发生和死亡的风险。鉴于全球肥胖率的上升，更好地理解 肥胖促进PDAC进展的机制是必要的。为了研究肥胖是如何驱动PDAC的， 我们的实验室最近结合了一个公认的肥胖遗传模型和致癌的Kras驱动的胰腺 癌症模型，与非肥胖对照组相比，肿瘤负担增加，生存率下降。 肥胖小鼠胰腺中神经肽类激素CCK的异常表达 胰岛β(B)细胞，后者足以增强Kras驱动的胰腺肿瘤的发生。这些 结果揭示了肥胖驱动PDAC的一种新机制，即通过内分泌之间的局部激素信号转导 胰岛和外分泌腺泡细胞。因此，我的总体目标是阐明细胞和分子 胰岛对肥胖作出反应并进而促进PDAC进展的机制 通过内分泌-外分泌荷尔蒙信号。在Aim I中，我将进行体内和体内的血统追踪研究 用计算机识别导致b细胞错误表达激素的来源细胞，如CCK。在AIM II中，我 将确定b细胞识别所需的转录因子丢失是否会导致激素表达异常 在小鼠胰岛素瘤(胰岛素产生)细胞和原代人类b细胞中进行基因敲除实验 染色质免疫沉淀。最后，在目标三中，我将在体内进行功能获得和功能丧失 用腺相关病毒操纵胰岛特异性基因评价促肿瘤作用的实验 肥胖症中b细胞过度表达的cck以外的激素的可能性。总而言之，这些研究将 揭示新的内分泌适应，可以靶向阻止肥胖驱动的胰腺外分泌 肿瘤发生学。此外，通过在该项目中获得新的技术技能，广泛的指导 (来自她的赞助商、共同赞助商和合作者)，在杰出的科学环境中的互动， 参加高级课程和工作坊，以及出席和介绍会议和 通过研讨会，综合培训计划将显著拓宽申请者的技能，为成为 成功的独立研究科学家。

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death and soon to become the second in the next few years. Numerous epidemiologic studies have shown that obesity increases the risk of developing and dying of PDAC. Given the rise in worldwide obesity rates, a better understanding of the mechanisms by which obesity promotes PDAC progression is necessary. To study how obesity drives PDAC, our lab recently combined a well-established genetic model of obesity with an oncogenic Kras-driven pancreatic cancer model and showed increased tumor burden and decreased survival compared to non-obese controls. Obese mice exhibited aberrant expression of the neuropeptide hormone cholecystokinin (CCK) in pancreatic islet beta (b) cells, the latter of which was sufficient to enhance Kras-driven pancreatic tumorigenesis. These results uncovered a novel mechanism of obesity-driven PDAC by local hormonal signaling between endocrine islets and exocrine acinar cells. Therefore, my overall goal is to elucidate the cellular and molecular mechanisms by which islets adapt in response to obesity and in turn promote PDAC progression through endocrine-exocrine hormonal signaling. In Aim I, I will perform lineage tracing studies in vivo and in silico to identify the cell-of-origin that gives rise to b cells mis-expressing hormones, such as CCK. In Aim II, I will determine whether loss of transcription factors required for b cell identify lead to aberrant hormone expression in mouse insulinoma (insulin-producing) cells and primary human b cells using genetic knockdown experiments and chromatin immunoprecipitation. Lastly, in Aim III, I will perform in vivo gain-of-function and loss-of-function experiments using islet specific gene manipulation by adeno-associated viruses to evaluate the pro-tumorigenic potential of hormones beyond CCK that are overexpressed in b cells in obesity. Together, these studies will reveal novel endocrine adaptations that could be targeted to halt obesity-driven pancreatic exocrine tumorigenesis. In addition, through the acquisition of new technical skills in this project, extensive mentorship (from her sponsor, co-sponsor, and collaborators), interactions within an outstanding scientific environment, participating in advanced classes and workshops, and attendance and presentation at conferences and seminars, the comprehensive training plan will markedly broaden the applicant’s skillset in preparation to be a successful independent research scientist.