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度炎症促进肿瘤发生的机制见解。我们最近还发现了肥胖和癌症恶性肿瘤之间的潜在联系，其中侵袭性癌细胞表现出高水平的游离脂肪酸，这些游离脂肪酸反过来转化为致癌信号脂质，如溶血磷脂酸和胡萝卜素，这反过来驱动癌症的侵袭性特征。我们先前表明，一种在多种人类侵袭性癌细胞和原发性肿瘤中上调的酶，单酰基甘油脂肪酶（MAGL），驱动游离脂肪酸的这种脂解释放，并且阻断MAGL抑制脂肪酸释放和随后的LPA和胰高血糖素的形成，从而抑制癌细胞侵袭性和肿瘤生长。然而，非常明显的是，这些癌症致病性的缺陷被体外添加外源性脂肪酸或体内高脂饮食所挽救，从而产生了一个有趣的假设，即AGL在向癌细胞提供FFA中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传导脂质组分需要脂肪酸转运到细胞中以及将脂肪酸单元掺入复合脂质中的酶促过程，从而产生靶向这些FFA转运或代谢途径用于治疗干预以阻止对癌症的肥胖相关作用的可能性。该提案将利用先进的代谢组学方法绘制将膳食脂肪重塑为促肿瘤信号脂质以驱动癌症恶性的代谢途径。 公共卫生相关性：流行病学研究表明，肥胖导致结肠癌、乳腺癌、子宫内膜癌、肾癌、食道癌、贲门癌、胰腺癌、胆囊癌和肝癌以及可能的其他癌症的发病率和/或死亡率增加。这项提案将研究膳食脂肪是否可以直接被癌细胞吸收，并被重塑为复杂的脂质，从而刺激癌症的恶性程度和致瘤性。

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. PUBLIC HEALTH RELEVANCE: Epidemiological studies indicate that adiposity contributes to the increased incidence and/or death from cancers of colon, breast, endometrium, kidney, oesophagus, gastric cardia, pancreas, gallbladders, and liver, and possibly other cancers. This proposal will investigate whether dietary fat can be directly taken up by cancer cells to be remodeled into complex lipids which can in-turn stimulate cancer malignancy and fuel tumorigenicity.