Role of NSD3 in regulation of cancer pathogenesis

摘要 我们的首要目标是阐明该药物的作用模式，并评估其治疗潜力。 表观遗传调控因子NSD3在肺鳞癌发病机制中的调控作用肺 癌症是美国和全世界与癌症相关的死亡的最常见原因，导致超过 每年有180万人死亡。LUSC是第二种最常见的肺癌亚型，约占30% 不幸的是，仅在美国，每年就有超过4万人死亡。虽然新的靶向治疗已经 不幸的是，在其他恶性肿瘤中显示出希望，到目前为止，还没有批准的靶向治疗LUSC。 因此，有一个重大的未得到满足的需求，即发现新的、临床上可操作的和引人注目的靶点 开发最终治疗这种疑难疾病的新药。这里要检验的一个中心假设是 组蛋白H3赖氨酸36(H3K36)二甲基转移酶NSD3是一种很有前途的表观遗传学靶点 LUSC的治疗。在前期工作中，我们发现在LUSC中普遍扩增的NSD3是一种 在这种癌症的小鼠和人类模型中，LUSC致病的主要驱动因素。在我们的提案中，我们将 研究NSD3-H3K36me2轴在体内肺癌中的作用并探讨其分子和表观遗传学 NSD3驱动的肿瘤发生的基础。 目的1探讨NSD3在LUSC发病机制中的作用。我们已经开发出了新的老鼠模型 这概括了人类LUSC中最常见的基因变化，包括NSD3扩增，以及 加入了可诱导的双重组酶方法，以允许在体内研究多步骤肿瘤发生。这 该系统将被用来剖析NSD3在LUSC肿瘤起始、进展、 使用有条件的NSD3功能获得和基因敲除小鼠维持和转移转移。一个多步骤 该方法还将使NSD3作为晚期LUSC潜在治疗靶点的遗传学验证成为可能，这是一个阶段 迫切需要新的治疗方法。在目标2中，我们将阐明表观遗传途径。 NSD3-H3K36me2轴，利用新的尖端表观基因组技术。我们还将探讨 NSD3在单细胞水平促进人和小鼠LUSC模型的肿瘤内异质性。 总之，这项工作将是第一次评估NSD3的治疗潜力和作用机制。 LUSC.

ABSTRACT Our overarching goal is to elucidate the mode of action of and evaluate the therapeutic potential of the epigenetic regulatory factor NSD3 in the regulation of lung squamous cell carcinoma (LUSC) pathogenesis. Lung cancer is the most common cause of cancer-related mortality in the United States and worldwide, leading to over a 1.8 million deaths each year. LUSC is the second most common subtype of lung cancer, accounting for ~30% of all cases and tragically over 40,000 deaths each year in the US alone. While new targeted therapies have shown promise in other malignancies, unfortunately, to date, there are no approved targeted therapies for LUSC. Thus, there is a major unmet need to uncover new, clinically actionable, and compelling targets for the development of new medicines to ultimately treat this difficult disease. A central hypothesis to be tested here is that the histone H3 lysine 36 (H3K36) di-methyltransferase enzyme NSD3 is a promising epigenetic target for the treatment of LUSC. In preliminary work we found that NSD3, which is commonly amplified in LUSC, is a major driver of LUSC pathogenesis in mouse and human models of this cancer. In our proposal, we will investigate the role of the NSD3-H3K36me2 axis in lung cancer in vivo and explore the molecular and epigenetic basis of NSD3-driven tumorigenesis. In Aim 1 we investigate the role of NSD3 in LUSC pathogenesis. We have developed novel mouse models that recapitulate the most common genetic alterations in human LUSC, including NSD3 amplification, and incorporated an inducible dual-recombinase approach to allow study of multi-step tumorigenesis in vivo. This system will be used to dissect the specific functions for NSD3 in LUSC tumor initiation, progression, maintenance, and metastatic transition using conditional NSD3 gain-of-function and knockout mice. A multistep approach will also enable genetic validation of NSD3 as potential therapeutic target in advanced LUSC, a stage for which new therapies are urgently needed. In Aim 2 we will elucidate the epigenetic pathways reguated by the NSD3-H3K36me2 axis, utilizing new cutting-edge epigenomic technologies. We will also explore the role of NSD3 in promoting intratumoral heterogeneity in human and mouse models of LUSC at the single cell level. Together, this work will be the first to evaluate the therapeutic potential and mechanism-of-action of NSD3 in LUSC.