Ferroptosis and Cancer Cell Signaling

铁死亡和癌细胞信号转导

• 批准号: 10559537
• 负责人: Xuejun Jiang
• 金额: $ 44.79万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559537
• 关键词: Apoptosis; Apoptotic; Automobile Driving; Biochemical; Bioinformatics; Biological; Biology; Cancer Patient; Candidate Disease Gene; Cell Adhesion Molecules; Cell Death; Cells; Clinical; Communication; Development; Disease; Down-Regulation; E-Cadherin; Epithelial Cells; Epithelium; Event; Future; Gastric Adenocarcinoma; Gene Mutation; Genes; Genetic Transcription; Genetically Engineered Mouse; Grant; Investigation; Iron; Lipid Peroxidation; Malignant - descriptor; Malignant Neoplasms; Mediating; Mesenchymal; Mesothelioma; Metabolism; Missense Mutation; Modality; Molecular; Mutate; Mutation; Neoplasm Metastasis; Neurofibromin 2; Oncogenic; Oncoproteins; Organoids; Pathologic; Pathway interactions; Patients; Play; Precision therapeutics; Predisposition; Property; Publishing; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Structure; TFRC gene; Testing; The Cancer Genome Atlas; Therapeutic; Transcription Coactivator; Tumor Suppression; Tumor Suppressor Proteins; Validation; Work; Xenograft Model; Xenograft procedure; biomarker identification; cancer cell; cancer genomics; cancer therapy; carcinogenesis; clinically significant; effective therapy; gastric cancer cell; genetic approach; genome-wide; genomic data; in vivo; inhibitor; insight; loss of function; loss of function mutation; malignant stomach neoplasm; mouse model; mutant; novel; pharmacologic; pre-clinical; predict responsiveness; predictive marker; promoter; screening; specific biomarkers; success; tumor; tumorigenesis

Ferroptosis and Cancer Cell Signaling Summary Programmed cell death (PCD) plays important role in normal biology, and its deregulation contributes to the development of various diseases. Ferroptosis is a PCD modality driven by cellular metabolism and iron- dependent cellular lipid peroxidation. Mounting evidence indicates that ferroptosis is involved in multiple pathological conditions, including cancer. Therefore, understanding the mechanisms of ferroptosis is important for both fundamental biology and disease treatment. While most mechanistic investigation of ferroptosis focuses on intracellular molecular events, our recent studies revealed a conceptually novel mechanism for ferroptosis regulation that is non-cell autonomous: in epithelial cells, E-cadherin-mediated intercellular interaction suppresses ferroptosis through intracellular Merlin/NF2-Hippo signaling; antagonizing this signaling axis unleashes the activity of the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis through regulating multiple ferroptosis modulators. As E- cadherin and Hippo-YAP signaling are key regulators of epithelial mesenchymal transition (EMT), our work provides mechanistic insights into the recently published observation that mesenchymal and metastatic properties of cancer cells are highly correlated with the sensitivity of cancer cells to ferroptosis induction. Our preliminary studies furthersuggest that malignant mutation of E-cadherin and multiple components in the Merlin- Hippo-YAP signaling pathway can be used as biomarkers predicting cancer cell responsiveness to future ferroptosis-inducing therapies. Considering that loss of function mutations of tumor suppressors E-cadherin, NF2, and Lat1/2 (components of Hippo signaling), as well as super-activation of YAP oncoprotein, are all malignant events that make cancer cells more resistant to common therapies and to apoptotic cell death, our finding that these same mutations instead render cancer cells more sensitive to ferroptosis induction is unexpected and highly important both conceptually and clinically. Based on these preliminary results, in this proposal, (1) intercellularly, we will investigate the molecular basis underlying the role of E-cadherin in transducing signals into the intracellular machinery, thus functioning as both a tumor suppressor and counter-intuitively, an inhibitor of ferroptosis; to further expand this concept, we will determine if other cell adhesion molecules can also regulate ferroptosis via similar mechanism; (2) intracellularly, we will determine how YAP dictates ferroptosis sensitivity via its transcription co-regulating activity; and (3) relevant to cancer, as E-cadherin mutation is highly frequent in gastric cancer, a fatal disease currently without effective treatment, we will investigate the role of E-cadherin tumor suppressor in determining gastric cancer cell sensitivity to ferroptosis, and the potential role of E-cadherin-regulated ferroptosis in gastric cancer metastasis. Genetically engineered mouse models for gastric cancer, as well as gastric cancer patient- derived tumor organoids and xenograft mouse models, will be used for this preclinical investigation. Taken together, success of the proposed research will unveil in-depth mechanisms of ferroptosis, as well as its functional communication with various cancer-relevant intercellular and intracellular molecular events. The proposed research will also lead to the identification of biomarkers that predict cancer responsiveness to future ferroptosis-inducing cancer therapy.

铁凋亡与癌细胞信号转导 总结 细胞程序性死亡（PCD）在正常生物学中起着重要作用，其失调导致了细胞凋亡。 各种疾病的发展。铁凋亡是由细胞代谢和铁- 依赖细胞脂质过氧化作用。越来越多的证据表明，铁下垂涉及多个 病理状况，包括癌症。因此，了解铁凋亡的机制是重要的 用于基础生物学和疾病治疗。 虽然大多数铁凋亡的机制研究集中在细胞内的分子事件，我们最近的 研究揭示了一种概念上新颖的非细胞自主的铁凋亡调节机制： 上皮细胞，E-钙粘蛋白介导的细胞间相互作用通过细胞内抑制铁凋亡 Merlin/NF 2-Hippo信号传导;拮抗该信号传导轴释放原癌基因的活性， 转录共激活因子雅普通过调节多种铁凋亡调节剂来促进铁凋亡。作为E- 钙粘蛋白和Hippo-YAP信号是上皮间质转化（EMT）的关键调节因子，我们的工作 提供了最近发表的观察，间充质和转移的机制的见解， 癌细胞的特性与癌细胞对铁凋亡诱导的敏感性高度相关。我们 初步研究进一步表明，恶性突变的E-钙粘蛋白和多种成分在梅林- Hippo-YAP信号通路可用作预测癌细胞对未来免疫应答的生物标志物。 铁中毒诱导疗法。考虑到肿瘤抑制因子E-cadherin的功能缺失突变， NF 2和Lat 1/2（Hippo信号传导的组分）以及雅普癌蛋白的超活化，都是 恶性事件使癌细胞对普通疗法和凋亡性细胞死亡更有抵抗力，我们 发现这些相同的突变反而使癌细胞对铁凋亡诱导更敏感， 在概念上和临床上都是出乎意料的和非常重要的。 基于这些初步结果，在本建议中，（1）在细胞间，我们将研究分子 E-cadherin在将信号转导到细胞内机制中的作用的基础， 既是一种肿瘤抑制剂，又是一种反直觉的铁细胞下垂抑制剂;为了进一步扩展这一概念，我们 将确定其他细胞粘附分子是否也可以通过类似的机制调节铁凋亡;（2） 在细胞内，我们将确定雅普如何通过其转录共调控调控铁凋亡敏感性 活性;和（3）与癌症相关，因为E-钙粘蛋白突变在胃癌（一种致命疾病）中高度频繁 目前没有有效的治疗方法，我们将研究E-cadherin肿瘤抑制因子在确定 胃癌细胞对铁凋亡的敏感性，以及E-钙粘蛋白调节的铁凋亡在胃癌中的潜在作用 癌症转移基因工程小鼠胃癌模型，以及胃癌患者- 衍生的肿瘤类器官和异种移植小鼠模型将用于本临床前研究。采取 总之，拟议研究的成功将揭示铁凋亡的深入机制，以及其 与各种癌症相关的细胞间和细胞内分子事件的功能通信。的 拟议的研究还将导致识别生物标志物，预测癌症对未来癌症的反应。 铁中毒诱导癌症疗法。