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急剧损失为特征的消耗综合征，可能是癌症病理生理学中最不了解的特征。尽管其对患者的发病率和死亡率有重大影响，但对潜在机制的理解是相当原始的。虽然啮齿动物肿瘤移植模型激发了现有的见解，但肿瘤信号传导和宿主反应的共同原则仍然模糊不清，这种空白限制了有效疗法的发展。面对这样的困惑，果蝇可以作为一个简化但强大的替代模型。通过果蝇遗传学，可以很容易地创造出与人类癌症特征相同的恶性过度生长，而且果蝇对癌症生物学的贡献有着直接相关的记录。我们发现，引入野生型宿主的苍蝇肿瘤可以在外周宿主组织中诱导戏剧性的消耗样反应，包括组织质量损失和营养信号改变。本申请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则，并推进对肿瘤-宿主组织相互作用的总体了解。我们将首先利用对果蝇信号传导生物学的丰富理解（包括功能必要性/充分性分析）来确定诱导宿主组织中消耗反应的途径。接下来，我们将测试炎症和基于改变的营养信号的浪费模型。然后，我们将发现或排除肿瘤产生的信号作为宿主组织浪费的煽动者，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浪费。最后，我们将探讨在果蝇中发现的机制对哺乳动物恶病质模型的适用性。这一提议代表了在非哺乳动物系统中对恶病质的首次调查，具有旗舰模型遗传生物体所能带来的所有实验能力。尽管苍蝇和人类及其癌症之间存在许多差异，但这个高风险/高收益项目具有很强的潜力来揭示组织浪费的基本和保守途径，这可能会澄清该领域目前的混乱，并产生新的研究方向。

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 We will then uncover or rule out tumor-produced signals as instigators of host tissue wasting, leveraging unpublished transcriptome datasets from tumors that can and cannot induce wasting.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.