PQ6 MECHANISMS OF CACHEXIA LIKE WASTING IN A DROSPHILA CANCER MODEL

描述（由申请人提供）：癌症恶病质，一种以骨骼肌和脂肪组织的显著损失为特征的消耗综合征，可能是癌症病理生理学中最不为人所知的特征。尽管它对患者发病率和死亡率有重大影响，但对其潜在机制的理解相当原始。虽然啮齿动物肿瘤移植模型已经激发了现有的见解，但肿瘤信号传导和宿主反应的共同原理仍然不清楚，这一空白限制了有效治疗方法的发展。面对这样的困惑，果蝇可以作为一个简化论者，但又强大的替代模型。与人类癌症有共同特征的恶性过度生长可以很容易地通过果蝇的基因产生，而且果蝇在癌症生物学方面有着直接相关的贡献记录。我们已经发现，将苍蝇肿瘤引入野生型宿主体内，可以在宿主周围组织中诱导出戏剧性的浪费样反应，包括组织质量的损失和营养信号的改变。本应用程序的具体目的是确定潜在的机制，目的是发现人类癌症恶病质的共同原理，并推进对肿瘤-宿主组织相互作用的了解。我们将首先利用对果蝇信号生物学的丰富理解（包括功能必要性/充分性分析）来确定宿主组织中诱导消耗反应的途径。接下来，我们将测试炎症和基于营养信号改变的消耗模型。然后，我们将发现或排除肿瘤产生的信号作为宿主组织消耗的煽动者，利用来自肿瘤的未发表的转录组数据集，这些数据集可以和不能诱导消耗。最后，我们将研究在果蝇中发现的机制在哺乳动物恶病质模型中的适用性。这一提议代表了在非哺乳动物系统中对恶病质的首次研究，具有旗舰模式遗传生物所能带来的所有实验力量。尽管果蝇和人类及其癌症之间存在许多差异，但这一高风险/高收益的项目具有很强的潜力，可以揭示组织消耗的基本和保守途径，这可能会澄清目前该领域的混乱，并为研究提供新的方向。

DESCRIPTION (provided by applicant): Cancer cachexia, a wasting syndrome characterized by the dramatic loss of skeletal muscle and adipose tissue, is perhaps the most poorly understood feature of cancer pathophysiology. Despite its major impact on patient morbidity and mortality, an understanding of the underlying mechanisms is quite primitive. While rodent tumor graft models have spurred existing insight, common principles of tumor signaling and host response remain obscure, and this void has limited development of effective therapies. In the face of such confusion, Drosophila can serve as a reductionist yet powerful alternative model. Malignant overgrowths that share features of human cancer can be readily created via Drosophila genetics, and the fly has a track record of contributions directly relevant to cancer biology. We have discovered that fly tumors introduced into wild-type hosts can induce a dramatic wasting-like response in peripheral host tissues, including loss of tissue mass with altered trophic signaling. The specific aim of this application is to identify the underlying mechanisms, with the goal of discovering common principles with human cancer cachexia and advancing insight into tumor-host tissue interactions in general. We will first capitalize on the rich understanding of Drosophila signaling biology (including functional necessity/sufficiency assays) to determine the pathways inducing wasting response in host tissues. We will next test both inflammation and altered nutrient signaling-based models for wasting. We will then uncover or rule out tumor-produced signals as instigators of host tissue wasting, leveraging unpublished transcriptome datasets from tumors that can and cannot induce wasting. Finally, we will investigate the applicability of the mechanisms uncovered in Drosophila to mammalian cachexia models. This proposal represents the first investigation of cachexia in a non-mammalian system, with all the experimental power that the flagship model genetic organism can bring. Despite the many differences between flies and humans and their cancers, this high-risk/high-gain project has strong potential to uncover fundamental and conserved pathways of tissue wasting, which could bring clarity to current confusion in the field and generate new directions for investigation.