The role of NSD1 inactivation in the development and treatment of oral squamous cell carcinoma

点击翻译按钮获取中文摘要

Project Summary: Head and neck squamous cell carcinoma (HNSCC) is a physically disfiguring and often fatal disease, of which the oral cavity is the most common site. Most HNSCC patients will die within the first 30 months of disease, an abysmal statistic largely reflecting a lack of effective treatment strategies. This challenge highlights the current unmet need to identify 1) distinct molecular subgroups of HNSCC and 2) prognostic biomarkers that can inform subgroup-specific treatment plans. My lab has identified a previously unappreciated HNSCC subgroup defined by alteration in NSD1, a histone methyltransferase enzyme mutated in up to 15% of HPV(-) HNSCC. NSD1 has specific di-methylase activity targeting histone H3 lysine 36 (H3K36). The formation of methylated H3K36 is associated with open chromatin and transcriptional activation. There are several distinct features of NSD1- mutant HPV(-) HNSCC tumors, including a) increased patient smoking history and mutational burden; b) a significantly better prognosis; and c) reduced immune cell infiltration in the tumor. These correlative findings suggest a role of NSD1 in modulating HNSCC tumor responsiveness to chemotherapeutics and immune- targeting treatments, yet the causal relationship and the underlying mechanism remain unclear. Building on our preliminary results and the combined expertise of my sponsors and consultants, my proposal will test the central hypothesis that NSD1-inactivation facilitates the development of oral squamous cell carcinomas that are poorly immune-infiltrated and sensitive to treatment with cisplatin. To model NSD1 loss in oral squamous carcinogenesis, I have generated conditional Nsd1 knockout (KO) mice to specifically delete NSD1 in the tongue epithelium. In Aim 1, I will use this model to test the hypotheses that inactivation of NSD1 (a) accelerates HNSCC development and (b) generates tumors that are both genomically unstable and contain low levels of immune cell infiltration. In Aim 2, I will investigate the observation that NSD1-mutant HNSCC patients live longer, which is hypothesized to reflect enhanced sensitivity to cisplatin. I will determine if cisplatin treatment provides a survival benefit in tumor-bearing Nsd1 KO mice. To better understand the underlying mechanism, I will perform ChIP-seq of NSD1 and ATAC-seq to test our hypothesis that NSD1 directly binds to, or close to, genes in the Fanconi anemia pathway, leading to H3K36me2 enrichment and a more accessible chromatin state. The proposed research is expected to broaden our understanding of NSD1’s tumor suppressive function in HPV(-) HNSCC and to establish NSD1 as a clinically useful biomarker to guide HNSCC treatment. This project also provides an ideal training opportunity for me to obtain conceptual understanding and experimental skills in the areas of oral pathology, mouse genetics and chromatin biology. Combined with my previous background, this proposal will facilitate my career development to become an independent physician-scientist focusing on dissecting genetic mechanisms underlying craniofacial and oral cavity diseases.