Transcriptional Profiling Reveals Mesenchymal Subtypes of Small Cell Lung Cancer with Activation of the Epithelial-to-Mesenchymal Transition and Worse Clinical Outcomes

SIMPLE SUMMARY: The aim of this study is to discover and characterize novel small cell lung cancer (SCLC) subtypes and further identify their relationship with existing SCLC subtypes. We identified SCLC-M (mesenchymal) tumors as SCLC subtypes that are distinctive of SCLC-I (inflamed) tumors. SCLC-M tumors showed elevated epithelial-to-mesenchymal transformation (EMT) activity but a low level of anticancer immune activity also with unfavorable clinical outcomes. Gene expression- and immunohistochemistry-based prediction suggests that SCLC-M tumors comprise approximately 5% of primary SCLC tumors. Given these unique molecular and clinical features, SCLC-M tumors should be taken into account in the clinical settings of SCLC management. ABSTRACT: While molecular subtypes of small cell lung cancers (SCLC) based on neuroendocrine (NE) and non-NE transcriptional regulators have been established, the association between these molecular subtypes and recently recognized SCLC-inflamed (SCLC-I) tumors is less understood. In this study, we used gene expression profiles of SCLC primary tumors and cell lines to discover and characterize SCLC-M (mesenchymal) tumors distinct from SCLC-I tumors for molecular features, clinical outcomes, and cross-species developmental trajectories. SCLC-M tumors show elevated epithelial-to-mesenchymal transformation (EMT) and YAP1 activity but a low level of anticancer immune activity and worse clinical outcomes than SCLC-I tumors. The prevalence of SCLC-M tumors was 3.2–7.4% in primary SCLC cohorts, which was further confirmed by immunohistochemistry in an independent cohort. Deconvoluted gene expression of tumor epithelial cells showed that EMT and increased immune function are tumor-intrinsic characteristics of SCLC-M and SCLC-I subtypes, respectively. Cross-species analysis revealed that human primary SCLC tumors recapitulate the NE-to-non-NE progression murine model providing insight into the developmental relationships among SCLC subtypes, e.g., early NE (SCLC-A and -N)- vs. late non-NE tumors (SCLC-M and -P). Newly identified SCLC-M tumors are biologically and clinically distinct from SCLC-I tumors which should be taken into account for the diagnosis and treatment of the disease.