Functional roles of GOF TP53 mutations in metastasis and immunosuppression of head and neck cancers

GOF TP53突变在头颈癌转移和免疫抑制中的功能作用

• 批准号: 10617289
• 负责人: Jeffrey Nicholas Myers
• 金额: $ 55.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-03 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617289
• 关键词: Alkylating Agents; B-Cell Activation; Cells; Chromosomal Instability; Complex; Cyclic GMP; DNA; DNA biosynthesis; Data; Development; Disease; Enhancers; Genes; Genomic Instability; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; IL8 gene; Immunosuppression; In Vitro; Incidence; Inflammation; Interferons; Interleukin-6; Invaded; Knowledge; Licensing Factor; Light; Link; MCM5 gene; Maintenance; Malignant Neoplasms; Mediating; Mutate; Mutation; Myeloid-derived suppressor cells; Neoplasm Metastasis; Nuclear; Patients; Poly(ADP-ribose) Polymerase Inhibitor; Production; Proliferating; Proteomics; Public Health; Replication Licensing; Reporting; Research; Resistance; Role; Signal Transduction; Stimulator of Interferon Genes; TP53 gene; Testing; Therapeutic; Tumor Cell Invasion; Tumor Immunity; Tumor Promotion; Work; cancer cell; carcinogenesis; chemokine; cytokine; cytotoxicity; design; effective therapy; gain of function; in vivo; innovation; mutant; novel; novel therapeutic intervention; prevent; replication stress; response; targeted treatment; temozolomide; treatment strategy; tumor; tumor progression; tumorigenesis; tumorigenic

Project Summary/Abstract TP53 is the most common somatically mutated gene among all cancers as it is altered in up to 85% of head and neck squamous cell carcinomas (HNSCC). Although TP53 mutations often lead to a loss of wild-type p53 (wtp53) function, many TP53 mutations confer mutant p53 (mutp53) gain-of-function (GOF), promoting cancer cell genomic instability, proliferation, invasion, metastasis, and cancer inflammation. However, the mechanisms involved in mutp53 GOF activity remain largely elusive, which is a major obstacle to fully understanding and targeting mutp53 to prevent tumorigenesis and tumor progression of HNSCC. Our long-term goal is to understand the role of TP53 mutations in promoting tumorigenesis and tumor progression of HNSCC and to use this knowledge to develop effective targeted therapies for HNSCC. The objective of this proposed research, which is the next step in pursuit of that goal, is to identify the specific role of GOF mutp53 in the promotion of chromosomal instability (CIN), which leads to tumor metastasis and immunosuppression, and to further exploit this to design novel treatment strategies for HNSCC. Our central hypothesis is that by targeting MCM5, a component of the replication licensing factor minichromosome maintenance 2-7 complex (MCM2-7), GOF mutp53 predisposes cells to CIN that leads to a STING-dependent cytosolic DNA response involving downstream activation of non-canonical nuclear factor kappa light chain enhancer of activated B cell (NF-κB) signaling, which, in turn, promotes tumor cell invasion, metastasis, and immunosuppression; therefore, targeting mutp53-mediated signaling can be used as a therapeutic strategy for HNSCC in patients with GOF TP53 mutations. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the functional roles of GOF mutp53-MCM5-cGAS/STING-non-canonical NF-κB signaling in the promotion of tumor invasion and metastasis in HNSCC cells; 2) Determine the functional roles of GOF mutp53- MCM5-cGAS/STING-non-canonical NF-κB signaling in the promotion of immunosuppression in HNSCC; 3) Identify novel therapeutic strategies for HNSCC with GOF p53 mutations. The research proposed in this application is highly innovative, given that the proposed mechanisms for studying GOF mutant p53 have never been reported before. Our hypothesis is based on our strong preliminary results from a proteomic screen of the mutp53 interactome, which uncovered a physical interaction between GOF mutp53 proteins and MCM5. We expect that the proposed work will identify intrinsic mechanisms of mutp53-mediated GOF in the promotion of genomic instability, metastasis, and immunosuppression that contribute to tumor development and tumor progression of HNSCC. Given the high incidence of p53 mutations in HNSCC, the proposed research is expected to have a significant impact on the public health burden of this deadly disease, and will help us develop novel therapeutic strategies to treat HNSCC patients with TP53 mutations.

项目摘要/摘要 TP53是所有癌症中最常见的体体突变基因，因为它在头部的85％中被改变，并且 颈部鳞状细胞癌（HNSCC）。尽管TP53突变通常会导致野生型p53（WTP53）的损失 功能，许多TP53突变会议突变体P53（MUTP53）功能获得（GOF），促进癌细胞 基因组不稳定性，增殖，侵袭，转移和癌症炎症。但是，机制 参与MUTP53 GOF活动仍然难以捉摸，这是完全理解和 靶向MUTP53以防止HNSCC的肿瘤发生和肿瘤进展。我们的长期目标是 了解TP53突变在促进HNSCC的肿瘤发生和肿瘤进展中的作用并使用 为HNSCC开发有效的有针对性疗法的知识。这项拟议研究的目的， 这是实现这一目标的下一步，是确定GoF Mutp53在促进中的特定作用 染色体不稳定性（CIN），导致肿瘤转移和免疫抑制，并进一步利用 这是为HNSCC设计新颖的治疗策略。我们的中心假设是通过靶向MCM5 复制许可因子的组成部分Minichromosom体维护2-7综合体（MCM2-7），GOF MUTP53易于将细胞倾向于CIN，导致依赖于STING的胞质DNA反应 非经典核因子Kappa轻链增强子的下游激活活化B细胞（NF-κB） 信号传导又促进了肿瘤细胞侵袭，转移和免疫抑制。因此，定位 MUTP53介导的信号传导可作为GOF TP53患者HNSCC的治疗策略 突变。在强大的初步数据的指导下，该假设将通过追求三个具体目标来检验：1） 确定GOF MUTP53-MCM5-CGAS/STING-NON-CANONICAR NF-κB信号在该中的功能作用 促进HNSCC细胞中肿瘤侵袭和转移； 2）确定GOF杂种的功能作用 MCM5-CGAS/STING-NON-CANONICAL NF-κB信号传导在HNSCC中促进免疫抑制中； 3） 确定具有GOF P53突变的HNSCC的新型热策略。这项研究提出了 鉴于研究GOF突变体p53的拟议机制从来没有 我们以前有报道。我们的假设是基于我们从蛋白质组学的强烈初步结果 MUTP53相互作用组，它发现了GOF MUTP53蛋白和MCM5之间的物理相互作用。我们 预计拟议的工作将确定促进豆p53介导的GOF的内在机制 基因组不稳定性，转移和免疫抑制，导致肿瘤发育和肿瘤 HNSCC的进展。鉴于HNSCC中p53突变的很高事件，预计拟议的研究是 要对这种致命疾病的公共卫生伯恩（Burnen）产生重大影响，并将帮助我们发展新颖 治疗HNSCC患者具有TP53突变的治疗策略。