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

基本信息

批准号：
10442206
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
项目类别：
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/10442206
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 Knowledge Lead Licensing Factor Light Link MCM5 gene Maintenance Malignant Epithelial Cell Malignant Neoplasms Mediating Mutate Mutation Myeloid-derived suppressor cells Neoplasm Metastasis Nuclear Patients Poly(ADP-ribose) Polymerases Production Proteins 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 base cancer cell carcinogenesis chemokine cytokine cytotoxicity design effective therapy gain of function in vivo inhibitor innovation mutant novel novel therapeutic intervention prevent replication stress response targeted treatment temozolomide treatment strategy tumor tumor progression tumorigenesis tumorigenic

项目摘要

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.

项目概要/摘要 TP53 是所有癌症中最常见的体细胞突变基因，因为它在高达 85% 的头部和癌症中发生改变。尽管 TP53 突变常常导致野生型 p53 (wtp53) 缺失，但颈部鳞状细胞癌 (HNSCC) 许多 TP53 突变赋予突变 p53 (mutp53) 功能获得性 (GOF)，促进癌细胞生长然而，基因组不稳定、增殖、侵袭、转移和癌症炎症的机制。参与 mutp53 GOF 活动的人在很大程度上仍然难以捉摸，这是充分理解和理解的主要障碍靶向 mutp53 来预防 HNSCC 的肿瘤发生和肿瘤进展。了解 TP53 突变在促进 HNSCC 肿瘤发生和肿瘤进展中的作用并利用这项研究的目的是开发针对 HNSCC 的有效靶向疗法。追求这一目标的下一步是确定 GOF mutp53 在促进染色体不稳定性（CIN），导致肿瘤转移和免疫抑制，并进一步开发我们的中心假设是通过靶向 MCM5，设计新的 HNSCC 治疗策略。复制许可因子微型染色体维护 2-7 复合物 (MCM2-7) 的组成部分，GOF mutp53 使细胞易患 CIN，从而导致 STING 依赖性胞质 DNA 反应，涉及激活 B 细胞的非经典核因子 kappa 轻链增强子 (NF-κB) 的下游激活信号传导，进而促进肿瘤细胞侵袭、转移和免疫抑制； mutp53 介导的信号传导可用作 GOF TP53 患者 HNSCC 的治疗策略在强有力的初步数据的指导下，该假设将通过追求三个具体目标进行检验：1）确定 GOF mutp53-MCM5-cGAS/STING-非经典 NF-κB 信号传导在 2) 确定GOF mutp53-的功能角色 MCM5-cGAS/STING-非经典 NF-κB 信号传导促进 HNSCC 的免疫抑制 3)；确定具有 GOF p53 突变的 HNSCC 的新治疗策略。鉴于所提出的研究 GOF 突变体 p53 的机制从未我们的假设是基于我们对蛋白质组筛选的强有力的初步结果。 mutp53 相互作用组，揭示了 GOF mutp53 蛋白和 MCM5 之间的物理相互作用。预计所提出的工作将确定 mutp53 介导的 GOF 在促进导致肿瘤发展和肿瘤发生的基因组不稳定、转移和免疫抑制鉴于 HNSCC 中 p53 突变的高发生率，拟议的研究是预期的。对这种致命疾病的公共卫生负担产生重大影响，并将帮助我们开发新的治疗携带 TP53 突变的 HNSCC 患者的治疗策略。