Project 2 NF-#B regulation in muscle wasting and pancreatic cancer-induced cachexia

项目总结：项目2 恶病质是一种衰弱的综合征，由于骨骼的耗尽而导致严重的、非自愿的体重减轻。 肌肉和脂肪组织。这种综合征发生在大多数癌症中，并导致大约一种 占所有癌症死亡人数的三分之一。目前，还没有有效的治疗方法来对抗这种恶性疾病。对于胰腺来说 导管腺癌(PDAC)是胰腺癌中侵袭性最强的一种，其潜在的益处是有效的 恶病质的治疗甚至可能比其他恶病质相关的恶性肿瘤更有效，因为其中85% 患者平均体重下降14%，恶病质极大地限制了他们的耐受能力。 手术、化疗或放射治疗。新的治疗方法可能会从对这种疾病的进一步了解中进化出来 导致肌肉萎缩和肿瘤发展的机制(恶病质的主要驱动因素)。本节目 该项目汇集了骨骼肌、肿瘤学、免疫学和恶病质方面的专家研究人员，以探索 核因子-B/IL-6/STAT3信号轴在癌症恶病质大环境中的作用--考虑两者 肌肉丢失的机制和PDAC的发展。在本计划的项目2中，重点将放在 这个信号轴的核因子-B部分。最近的努力集中在两个新概念上。第一个是 癌症恶病质与肌肉干细胞的激活有关，肌肉干细胞启动肌肉修复过程 纤维。核因子-B在干细胞中被激活，其功能是阻止修复并通过 调节局部肌肉炎症状态。第二个发现提供了对NF-B如何 在PDAC发展过程中肿瘤细胞内的功能。使用胰腺癌的小鼠模型，我们 研究表明，NF-B在保护肿瘤细胞免受抗肿瘤监视作用方面起着关键作用 巨噬细胞和细胞毒性T细胞。核因子-B能抑制先天免疫和获得性免疫 免疫抑制细胞因子GDF15的调节。这个项目的目标是探索这样一种假设 核因子-B通过作用于肌肉干细胞阻断肌肉在癌症恶病质大环境中的作用 修复，以及通过产生免疫抑制基因，如GDF-15，促进PDAC。 为了实现这一目标，我们试图实现以下两个具体目标：1)确定NF-B的相关性 调节癌症恶病质的肌肉炎症；以及2)确定NF-B如何调节GDF15和 免疫调节促进PDAC。实现这一目标将增进我们对核问题相关性的理解-- B以及这个信号成分如何与IL-6和STAT3相交来调节肌肉萎缩和肿瘤 在癌症恶病质的大环境中发展。

PROJECT SUMMARY: PROJECT 2 Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle and adipose tissues. This syndrome occurs in a majority of cancers and contributes to approximately a third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic ductal adenocarcinoma (PDAC), the most aggressive formof pancreatic cancer, the potential benefit for effective cachexia therapies may be even greater than for other cachexia-associated malignancies, since 85% of these patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting and tumor development (the primary driver of cachexia). This program project brings together expert investigators in skeletal muscle, oncology, immunology, and cachexia, to explore the role an NF-B/IL-6/STAT3 signaling axis within the macroenvironment of cancer cachexia – considering both mechanisms of muscle loss and the development of PDAC. In Project 2 of this program, focus will be placed on the NF-B portion of this signaling axis. Recent efforts have centered on two new concepts. The first is that cancer cachexia associates with the activation of muscle stem cells initiating a repair pr ocess on the muscle fiber. NF-B is activated in stem cells, and functions to block repair and promote muscle wasting through the regulation of a local muscle inflammatory condition. The second discovery provides insight in how NF-B functions within the tumor cell during development of PDAC. Using a mouse model of pancreatic cancer, we showed that NF-B plays a critical role in protecting tumor cells from the surveillance property of anti-tumor macrophages and cytotoxic T cells. NF-B is able to suppress both innate and adaptive immunity through the regulation of the immunosuppressive cytokine, GDF15. The goal of this project is to explore the hypothesis that NF-B functions in the macroenvironment of cancer cachexia by acting in muscle stem cells to block muscle repair, as well as promoting PDAC through the production of immunosuppressive genes such as GDF-15. Towards this goal we seek to perform the following two specific aims: 1) Determine the relevance of NF-B regulation of muscle inflammation in cancer cachexia; and 2) Determine how NF-B regulation of GDF-15 and immune modulation promotes PDAC. Achieving this goal will enhance our understanding of the relevance of NF- B and how this signaling component intersects with IL-6 and STAT3 to regulate muscle wasting and tumor development within the macroenvironment of cancer cachexia.