Remodeling of Dietary Fat into Protumorigenic Signaling Lipids in Cancer (PQ1)

描述（由申请人提供）：肥胖与几乎所有癌症类型的癌症死亡率增加有关。最近的研究提供了关于肥胖如何通过增强胰岛素信号或低级别炎症促进肿瘤发生的机制见解。我们最近还发现了肥胖和恶性癌症之间的潜在联系，在这种联系中，侵袭性癌细胞表现出较高水平的游离脂肪酸，这些脂肪酸反过来转化为致癌信号脂质，如溶血磷脂酸和前列腺素，它们反过来驱动癌症的侵袭性特征。我们之前的研究表明，一种酶，单酰基甘油脂肪酶（MAGL），在多种人类侵袭性癌细胞和原发肿瘤中上调，驱动游离脂肪酸的脂解释放，阻断MAGL抑制脂肪酸释放和随后LPA和前列腺素的形成，从而抑制癌细胞的侵袭性和肿瘤生长。然而，令人兴奋的是，通过在体外添加外源性脂肪酸或在体内添加高脂肪饮食，这些癌症致病性缺陷得以挽救，这引发了一个有趣的假设，即AGL在为癌细胞提供FFAs方面的作用可以被外源性脂肪来源所取代。这种将外源性脂肪酸重塑为癌细胞的结构或信号脂质成分的过程既需要脂肪酸转运到细胞中，也需要将脂肪酸单位整合到复杂脂质中的酶促过程，因此有可能针对这些脂肪酸转运或代谢途径进行治疗干预，以阻止肥胖对癌症的相关影响。该建议将绘制代谢途径，利用先进的代谢组学方法将膳食脂肪重塑为致癌信号脂质，从而驱动恶性肿瘤。

DESCRIPTION (provided by applicant): Obesity has been linked to enhanced cancer mortality across almost all cancer types. Recent studies have provided mechanistic insights into how obesity can contribute to tumorigenesis through enhanced insulin signaling or low-grade inflammation. We have recently also uncovered a potential link between obesity and cancer malignancy in which aggressive cancer cells exhibit heightened levels of free fatty acids which in-turn are transformed into oncogenic signaling lipids, such as lysophosphatidic acid and prostaglandins, which in turn drive aggressive features in cancer. We previously showed that an enzyme, monoacylglycerol lipase (MAGL), upregulated across multiple human aggressive cancer cells and primary tumors, drives this lipolytic release of free fatty acids and that blockin MAGL suppressed fatty acid release and subsequent formation of LPA and prostaglandins leading to suppressed cancer cell aggressiveness and tumor growth. Quite provocatively, however, these defects in cancer pathogenicity were rescued by addition of exogenous fatty acids in vitro or high-fat diet in vivo, giving rise to the intriguing hypothesis that the role of AGL in supplying cancer cells with FFAs can be supplanted by exogenous sources of fat. This remodeling of exogenous fatty acids into either structural or signaling lipid components for the cancer cell requires both fatty acid transport into the cells and enzymatic processes that would incorporate fatty acids units into complex lipids, thereby giving rise to the possibility of targetng these FFA-transport or metabolic pathways for therapeutic intervention to thwart obesity-related effects on cancer. This proposal will map metabolic pathways that remodel dietary fat into protumorigenic signaling lipids to drive cancer malignancy using advanced metabolomic approaches.