Involvement of Epithelial–Mesenchymal Transition Genes in Small Cell Lung Cancer Phenotypic Plasticity

SIMPLE SUMMARY: Small cell lung cancer (SCLC) is an aggressive cancer that is difficult to treat. There are at least five subtypes of SCLC cells, defined by gene expression signatures. The transitions between these subtypes and cooperation between them contribute to the progression of SCLC. Particularly, transitions between neuroendocrine (NE) states, including A, A2, and N subtypes, and the non-NE states, including P and Y subtypes, are hallmarks of SCLC plasticity. In this study, the relationship between SCLC subtypes and epithelial to mesenchymal transition (EMT) was analyzed. EMT is a well-known form of cellular plasticity that contributes to cancer invasiveness and resistance. The results showed that the SCLC-A2 subtype is epithelial while SCLC-A and SCLC-N are mesenchymal but distinct from the non-NE mesenchymal states. This study provides a basis for understanding the gene regulatory mechanisms of SCLC tumor plasticity and its applicability to other cancer types. ABSTRACT: Small cell lung cancer (SCLC) is an aggressive cancer recalcitrant to treatment, arising predominantly from epithelial pulmonary neuroendocrine (NE) cells. Intratumor heterogeneity plays critical roles in SCLC disease progression, metastasis, and treatment resistance. At least five transcriptional SCLC NE and non-NE cell subtypes were recently defined by gene expression signatures. Transition from NE to non-NE cell states and cooperation between subtypes within a tumor likely contribute to SCLC progression by mechanisms of adaptation to perturbations. Therefore, gene regulatory programs distinguishing SCLC subtypes or promoting transitions are of great interest. Here, we systematically analyze the relationship between SCLC NE/non-NE transition and epithelial to mesenchymal transition (EMT)—a well-studied cellular process contributing to cancer invasiveness and resistance—using multiple transcriptome datasets from SCLC mouse tumor models, human cancer cell lines, and tumor samples. The NE SCLC-A2 subtype maps to the epithelial state. In contrast, SCLC-A and SCLC-N (NE) map to a partial mesenchymal state (M1) that is distinct from the non-NE, partial mesenchymal state (M2). The correspondence between SCLC subtypes and the EMT program paves the way for further work to understand gene regulatory mechanisms of SCLC tumor plasticity with applicability to other cancer types.