Role of NSD3 in regulation of cancer pathogenesis

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.