Ferroptosis, Cellular Metabolism, and Cancer

铁性下垂、细胞代谢与癌症 摘要 铁下垂是一种由细胞代谢和铁依赖的脂质引起的非凋亡性细胞死亡。 过氧化。尽管上睑下垂的生理作用仍不清楚，但越来越多的证据已经证实。 铁下垂会影响包括癌症在内的各种病理过程。这项竞争性的续签提案是 建立在我们在前一个资金周期中所取得的成就的基础上，旨在进一步阐明分子 铁下垂的基础，它与新陈代谢的相互作用，以及它在癌症中的作用。在上一个资助期，我们发现 多种细胞代谢途径，如自噬、谷氨酰胺分解，以及令人惊讶的是，正常代谢 线粒体的活动，导致铁中毒死亡。我们还发现，CdH1-NF2-Hippo-YAP和PI3K- AKT-mTOR-SREBP信号通路都与癌症高度相关，通过调节调节铁下垂 细胞铁稳态与脂类代谢。此外，通过全基因组CRISPR/Cas9-激活屏幕， 我们确定了几种脂类修饰酶作为新的铁下垂抑制因子，进一步强调了 脂代谢与铁性下垂的关系。重要的是，我们的TCGA分析表明过度表达 其中一种酶，MBOAT2，预测多种癌症类型的不良预后，包括肝癌， 膀胱癌和胰腺导管腺癌(PDAC)。根据这些初步结果，中央 该基金的假设是，脂质修饰调节癌细胞的新陈代谢、侵袭性和铁下垂， 通过调节细胞脂质储存和膜组成，并结合靶向MBOAT2 铁诱导下垂具有治疗癌症的潜力。来研究这一假说并定义 在潜在机制方面，我们将解决以下问题。首先，这些脂质是通过什么机制 修饰剂保护细胞免受铁性下垂的影响，它们是否通过改变特定的磷脂物种来指示脂质过氧化， 它们是否与SREBP沟通，SREBP是脂肪生成的主要转录调节因子，也是一种强有力的铁下垂 抑制者(AIM-1)？第二，这些脂质修饰剂是否调节细胞特性，如细胞存储 脂类作为能源与质膜可塑性？因为这些细胞特性会影响癌细胞 侵袭/转移能力、新陈代谢和可能的氧化还原动态平衡之间是否存在功能上的相互作用 铁下垂和这些与癌症相关的细胞过程(AIM-2)？第三，与癌症治疗直接相关 (AIM-3)，通过使用患者来源的肿瘤有机化合物、异种小鼠模型和基因工程小鼠 模型(GEMM)，我们将研究我们新发现的铁下垂抑制因子如何调节肿瘤形成， 转移和癌细胞对铁性下垂诱导的反应性，并评估联合 联合应用MBOAT2抑制和铁性下垂可作为治疗肺癌的有效方法。 MBOAT2的过度表达预示着预后不良(在本方案中，我们将重点关注PDAC)。成功之路 拟议的研究将导致对铁性下垂及其与细胞的相互作用的深入机制的理解 并为新的、基于机制的癌症疗法的发展提供了洞察力。

Ferroptosis, Cellular Metabolism, and Cancer Abstract Ferroptosis is a form of non-apoptotic cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although the physiological role of ferroptosis remains elusive, mounting evidence has established that ferroptosis impacts various pathological processes, including cancer. This competitive renewal proposal is built upon what we have achieved during the previous funding cycle and aims to further elucidate the molecular basis of ferroptosis, its interplay with metabolism, and its role in cancer. In the previous funding period, we found that multiple cellular metabolic pathways, such as autophagy, glutaminolysis, and strikingly, the normal metabolic activity of mitochondria, contribute to ferroptotic death. We also found that the CDH1-NF2-Hippo-YAP and PI3K- AKT-mTOR-SREBP signaling pathways, both highly relevant to cancer, regulate ferroptosis through modulating cellular iron homeostasis and lipid metabolism. Moreover, via a whole genome CRISPR/cas9-activation screen, we identified several lipid modifying enzymes as novel ferroptosis suppressors, further underscoring the intimate relationship between lipid metabolism and ferroptosis. Importantly, our TCGA analysis indicates overexpression of one of these enzymes, MBOAT2, predicts poor prognosis in multiple cancer types, including liver cancer, bladder cancer, and pancreatic ductal adenocarcinoma (PDAC). Based on these preliminary results, the central hypothesis of the grant is that lipid modification regulates cancer cell metabolism, invasiveness, and ferroptosis, through modulating cellular lipid storage and membrane composition; and targeting MBOAT2 in combination with ferroptosis induction holds cancer therapeutic potential. To investigate this hypothesis and to define the underlying mechanisms, we will tackle following questions. First, what is the mechanism by which these lipid modifiers protect cells fromferroptosis,do they dictate lipid peroxidation viaaltering specific phospholipidspecies, and do they communicate with SREBP, a master transcriptional regulator of lipogenesis and a potent ferroptosis suppressor (Aim-1)? Second, do these lipid modifiers modulate cellular properties such as cellular storage of lipids as energy source and plasma membrane plasticity? As these cellular properties impact cancer cell invasive/metastatic capability, metabolism, and likely redox homeostasis, is there a functional interplay between ferroptosis and these cancer-relevant cellular processes (Aim-2)? Third and directly relevant to cancer treatment (Aim-3), by using patient-derived tumor organoids, xenograft mouse models, and genetically engineered mouse models (GEMM), we will investigate how our newly-identified ferroptosis suppressors modulate tumorigenesis, metastasis and the responsiveness of cancer cells to ferroptosis induction, and assess whether the combination of MBOAT2 inhibition with ferroptosis induction can be an effective therapy for the treatment of cancer in which MBOAT2 overexpression predicts poor prognosis (we will focus on PDAC in this proposal). Success of the proposed study will lead to an in-depth mechanistic understanding of ferroptosis and its interplay with cellular metabolism, and provide insights into the development of novel, mechanism-based cancer therapies.