Analysis of transcriptome datasets reveals involvement of epithelial-mesenchymal transition genes in small cell lung cancer phenotypic plasticity

Small cell lung cancer (SCLC) is an aggressive cancer recalcitrant to treatment. SCLC arises in lung epithelium, and the phenotypic heterogeneity of SCLC cells plays critical roles in disease progression and drug resistance. Particularly, the transition from neuroendocrine (NE) cells to non-neuroendocrine (non-NE) cells, as well as the cooperations between these cell types, are observed in SCLC progression. At least five subtypes of SCLC tumors have recently been defined by signature gene expression and these subtypes have been extended to individual SCLC tumor cells. However, the molecular and cellular programs that distinguish the cell types or allow transitions among them are unclear. Here, we systematically analyzed the relationship between SCLC and epithelial to mesenchymal transition (EMT)—a cellular process well known to contribute to invasiveness and drug resistance of cancer cells—using multiple transcriptome datasets from a mouse tumor model, human cancer cell lines, and human tumor samples. Our analysis of these datasets consistently showed that an extreme epithelial state corresponds to the SCLC-A2 subtype. Furthermore, two NE subtypes have significant expression of a subset of mesenchymal genes, with surprisingly limited overlap with the mesenchymal genes highly expressed in non-NE cells. Our work reveals a previously unknown connection between an EMT program and a specific SCLC subtype and an underappreciated divergence of EMT trajectories contributing to the SCLC phenotypic heterogeneity. ### Competing Interest Statement V.Q. is an Academic co-Founder and equity holder for Parthenon Therapeutics, Inc. and Duet BioSystems, Inc. D.R.T. is on the Scientific Advisory Board of VRise Therapeutics. The other authors declare no conflict of interest.