The Effects of Ezh2 Mutation on Kras‐Driven Adenocarcinoma

Abstract

Lung cancer is the deadliest form of cancer worldwide. Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer, constituting an estimated 84% of diagnoses. Conducting research regarding the metastasis of lung adenocarcinomas is especially pertinent, as the 5‐year survival rate for localized NSCLC is an estimated 50% versus 6% in metastatic lung cancer. Here we investigate the activation effects of Polycomb Repressive Complex 2 (PRC2), an epigenetic regulator commonly found to be dysregulated in human lung cancer, as a driver of metastasis. We employed genetically engineered mouse models harboring activating point mutations in Kras and inactivating mutations in the p53 pathway (KP model) which develop lung adenocarcinomas but exhibit low penetrance and long latency for metastasis. As a resolution, our lab has generated a KPE mouse model which carries a mutation that induces Ezh2 activation, a core component of PRC2. We hypothesize that KPE is an effective and robust metastatic model which displays a shorter latency period than previously established lung adenocarcinoma models. In this project we used a histological approach to characterize morphological properties of primary tumors as well as distinct lymph node metastases in KPE mouse models. By visualizing cellular phenotypes through Hematoxylin & Eosin staining, we intended to quantify tumor area and composition of lymphatic micrometastases. The results illustrated that mice with the Ezh2 mutation in addition to the Kras and p53 mutations experienced a shorter latency period as well as a higher occurrence of lymph node metastases as opposed to the KP model.Support or Funding InformationThis project is supported in part by National Science Foundation Grant 1758007.