肿瘤分泌蛋白差异化调节机体糖和脂代谢的机制研究

The major features of cancer cachexia, a newly-recognized metabolic disorder, include loss of fat and muscle in patients with advanced malignant tumors. However, 50% of these patients exhibit early-stage glucose tolerance/hyperglycemia and its associated poor prognosis. The mechanisms how different types of tumors regulate lipid and carbohydrate metabolism in a differential manner is unknown. We have established a conserved fly model of tumor-induced lipid and carbohydrate imhomeostasis, by which induction of oncogene yki causes malignant gut tumors and lipid loss, glucose tolerance, as well as muscle injury, in the host organs and further demonstrated that tumors impair systemic metabolism via the production of secreted proteins. The mechanisms have been partially validated in human and mice. Our preliminary results reveal that yki tumors specifically impair carbohydrate metabolism without affecting lipid metabolism via the production of ITP (Ion Transport Peptide), a novel secreted protein that is absent in Ras1 tumors failing to affect systemic carbohydrate metabolism. In this study, we will combine mouse and fly models to study how ITP mediates tumor-induced host carbohydrate metabolic imbalance, including yki regulation of ITP synthesis and ITP downstream tissues and pathways, and elucidate the molecular mechanisms whereby tumors differentially modulate lipid and carbohydrate metabolism in host organs.

癌症恶液质是一种代谢疾病，表现为晚期恶性肿瘤患者的脂肪和肌肉消耗，但50%患者在早期出现糖耐受/高血糖而导致病情恶化，因此不同肿瘤差异化调节机体糖和脂代谢的机制是未知的。申请人曾建立肿瘤诱导机体糖脂代谢紊乱的果蝇模型，如癌基因yki诱发肠道恶性肿瘤和导致宿主脂肪流失、糖耐受和肌肉受损，并阐明肿瘤可释放分泌蛋白远程破坏机体糖脂代谢平衡，部分机制在人和小鼠中证实。申请人预实验发现：yki肿瘤可释放另一全新分泌蛋白ITP（Ion Transport Peptide）只引发糖耐受，而不影响脂代谢；且ITP在不造成机体糖耐受的Ras1肿瘤中缺失。在本项目中我们将结合小鼠和果蝇模型研究ITP如何介导肿瘤破坏机体糖代谢，包括yki对ITP的合成调控与ITP下游组织和通路的鉴定，揭示肿瘤差异化调节机体糖和脂代谢的分子机制。

维持肾功能和体液平衡对脊椎动物和无脊椎动物都至关重要，以此应对多种生理病理应激。恶性肿瘤患者频繁出现肾功能受损和尿少症，虽然有些研究表明化疗药的肾毒性以及炎症反应参与其中，但恶性肿瘤是否以及如何干扰肾功能仍旧大量未知，因此临床上目前只有透析这一种应对策略。我们构建了一种进化保守的果蝇肠癌模型，发现yki3SA肠道恶性肿瘤通过分泌一种名为ITP的分泌蛋白破坏肾脏功能，导致严重的体液堆积和腹部肿胀。有意思的是ITP是我们在昆虫系统中首次发现的抗利尿激素。在机制上，我们进一步揭示ITP靶向果蝇成虫的马氏管星状细胞，通过激活那里的GPCR受体TkR99D、启动Nos/cGMP通路，从而抑制体液排除。此外，我们也在哺乳动物中发现了TkR99D介导肿瘤破坏肾脏的利尿功能，因为用小分子抑制剂阻断TSP4R可以有效缓解恶性肿瘤引发的肾小管病变和排尿障碍。因此，我们的结果阐明了一条全新的、进化保守的抗利尿通路来介导“肿瘤-肾脏”互作，为癌症相关肾病提供了新的治疗理念。