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

项目摘要/摘要 TP53是所有癌症中最常见的体细胞突变基因，它在高达85%的头部和 颈部鳞癌(HNSCC)。尽管TP53突变经常导致野生型p53(Wtp53)的丢失 功能，许多TP53突变赋予突变型P53(突变P53)功能获得(GOF)，促进癌细胞 基因组不稳定、增殖、侵袭、转移和癌症炎症。然而，这些机制 参与突变p53 GOF活性在很大程度上仍然难以捉摸，这是充分了解和 靶向突变P53预防HNSCC的肿瘤发生和进展。我们的长期目标是 了解TP53突变在促进HNSCC发生和进展中的作用 这些知识有助于为HNSCC开发有效的靶向治疗方法。这项拟议研究的目标是， 这是追求这一目标的下一步，是确定GOF突变p53在促进 染色体不稳定(CIN)，导致肿瘤转移和免疫抑制，并进一步开发 这将为HNSCC设计新的治疗策略。我们的中心假设是，通过靶向MCM5，一个 复制许可因子微染色体维持2-7复合体(MCM2-7)的组成部分 突变p53使细胞对CIN易感，从而导致依赖于刺的胞浆DNA反应，包括 活化B细胞非典型核因子轻链增强子(NF-κB)的下游激活 信号转导，进而促进肿瘤细胞的侵袭、转移和免疫抑制；因此，靶向 突变p53介导的信号转导可作为治疗GOF TP53患者HNSCC的一种策略 突变。在强劲的初步数据的指导下，这一假说将通过追求三个具体目标来检验：1) 确定GOF突变的p53-MCM5-cGAS/STING-非规范的NF-κB信号在 促进HNSCC细胞的侵袭和转移；2)确定GOF-mutP53-1的功能作用 MCM5-cGAS/STING-非规范的NF-κB信号在促进肝细胞癌免疫抑制中的作用 确定具有GOF P53突变的HNSCC的新治疗策略。这项研究中提出的 应用具有很高的创新性，因为所提出的研究GOF突变体P53的机制从未 以前也有过报道。我们的假设是基于我们从蛋白质组筛查得出的强有力的初步结果 它揭示了GOF突变P53蛋白与MCM5之间的物理相互作用。我们 期望拟议的工作将确定突变P53介导的GOF在促进 导致肿瘤发展和肿瘤的基因组不稳定、转移和免疫抑制 HNSCC的进展。鉴于HNSCC中p53突变的高发生率，拟议的研究是可想而知的 对这种致命疾病的公共卫生负担产生重大影响，并将有助于我们开发新的 治疗TP53突变的HNSCC患者的治疗策略。

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.