Modelling the molecular link between high Fat diet, Metabolic reprogramming and Inflammation in Lung Cancer

三十年的癌症遗传学研究已经揭示了在大多数人类癌症中发生突变的显性癌症基因。在过去的十年里，癌症研究的一个重新出现的主导话题是，大多数实体肿瘤在其葡萄糖和脂质代谢方面经历了可重复的变化，这使得肿瘤细胞在营养限制的条件下能够疯狂生长和促进存活。人们不太了解的是，葡萄糖、果糖和脂肪的饮食和饮食对癌症遗传学的影响。西方饮食以及它们如何加速癌症的发展是本提案的主题。家庭委员会的重点是肺癌，这是欧洲男性和女性每年癌症死亡的最常见原因。肺癌的代谢谱在很大程度上是由特定的遗传驱动事件驱动的，并且高度依赖于重新合成脂肪酸。使用尖端脂质组学方法，我们的目标是了解高脂肪饮食在多大程度上与肿瘤细胞脂肪生成有关，有利于脂肪酸的氧化，以及遗传畸变如何调节这些联系。脂质，特别是特定种类的鞘脂，最近被证明是癌细胞生长的重要能量来源，影响癌细胞的侵袭性。此外，脂质是炎症介质前列腺素的主要来源。高脂饮食可以通过脂质代谢、氧化应激和免疫途径的失调，扰乱免疫反应，增加炎症细胞。这些不必要的炎症反应会影响下游细胞增殖、血管生成、肿瘤转移和化疗反应。FaMILC旨在解释西式饮食如何影响非小细胞肺癌的炎症反应和代谢，并与特定的遗传改变交叉以控制肿瘤进展。

Thirty years of cancer genetics have revealed the dominant cancer genes that are mutated in most forms of human cancer. What hasalso become a re-emergent dominant topic of cancer research in the past decade is that most solid tumours undergo reproduciblechanges in their glucose and lipid metabolism that enables rampant growth and foster survival of tumour cells in nutrient limitingconditions. What is less well-understood is how diet and dietary contributions of glucose, fructose and fats intersect with cancergenetics. Western diets and how they can speed cancer development are the topics of this proposal. FaMILC is focused on lungcancer, the most common cause of cancer deaths per year in men and in women in Europe. The metabolic profile of lung cancer isdriven in large part by specific genetic driver events and is highly dependent on de novo fatty acids synthesis. Using cutting edgelipidomic approaches, our goal is to understand to which extent high fat diet connects with tumour cell lipogenesis to favouroxidation of fatty acids and how genetic aberration modulate these links. Lipids, particularly specific classes of sphingolipids, haverecently been shown to be crucial sources of energy for cancer cell growth influencing cancer cell aggressiveness. Furthermore, lipidsare the main source for prostaglandins, mediators of inflammation. High fat diet can perturb immune responses and increaseinflammatory cells through dysregulation of lipid metabolism, oxidative stress and immune pathways. These unnecessaryinflammatory responses can affect downstream cell proliferation, angiogenesis, tumour metastasis and chemotherapeutic response.FaMILC aims to decipher how Western-style diet influences non-small cell lung cancer inflammatory responses and metabolismintersecting with specific genetic alterations to control tumour progression.