Lineage evolution of a small cell lung cancer epigenomic subtype signified by NKX2-1

PROJECT SUMMARY Lung cancer is the leading cause of cancer related deaths in the U.S. and worldwide. Large-scale genetic studies of lung cancer samples have discovered a number of important genetic changes that can be targeted as a treatment for lung cancer patients and led to significant improvement in outcome for patients with non-small cell lung cancers (NSCLC). In contrast, diagnosis, treatment and prognosis for patients with small cell lung cancer (SCLC), a more aggressive and widely metastatic subtype of lung cancer accounting for 15% of all lung cancer cases, have made little progress over the last decades with 5-year survival rate at a dismal 6-7%. Molecular understanding of SCLC pathogenesis also lags behind those of NSCLC. The current clinical classification of lung cancer still recognizes SCLC as a single disease. Recently, distinct molecular subtypes of SCLC have been identified that may explain diverse biological behaviors of SCLC and Achilles’ heel for development of new therapeutic potentials. SCLC is characterized by unique histological features of neuroendocrine differentiation and factors controlling this neuroendocrine state are now drawing attention for their roles in SCLC pathogenesis. Our group has been in the forefront of studying factors controlling differentiation in NSCLC through epigenetic analyses. Thus, to expand upon the current classification of SCLCs, we have employed our expertise to develop a new framework analyzing epigenetic profiles of SCLCs and we have identified two novel clusters within the major ASCL1- subtype that represent distinct identities. One of these clusters is signified by the presence of NKX2-1 super- enhancer and its expression is essential for evolving into this SCLC subtype. We hypothesize that this newly identified SCLC cluster, a sizable proportion of human SCLCs, defined by a dual pulmonary and neural lineage factor NKX2-1, represents a biological state potentially evolved through a distinct path. Thus, we aim to elucidate the mechanistic roles of lineage factors in distinct lineage subtypes of SCLCs using our expertise on transcriptional regulation and epigenomics by 1) determining how cell-of-origin and NKX2-1 impact evolution and maintenance of epigenomic SCLC states, 2) determining the mechanisms for pulmonary to neuronal adaptation in this SCLC subtype, and 3) determining the full spectrum of SCLC heterogeneity in human SCLCs and histological characteristics leveraging our access to a large collection of human SCLC specimens as well as patient-derived models.