Abstract 1295: Myc family members differentially regulate lineage plasticity in small cell lung cancer
Authors: Patel Ayushi S. , Yoo Seungyeul , Kong Ranran , Sato Takashi , Fridrikh Maya , Nudelman German , Powell Charles A. , Zhu Jun , Watanabe Hideo 
Published: September 2020

Abstract
Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer with a dismal prognosis. The standard-of-care remains to be uniform treatment with chemotherapy and radiotherapy, while emerging evidence suggests its molecular heterogeneity that has been previously under-appreciated. In primary SCLC, the gene loci for Myc family members are amplified mutually exclusively, their expression is correlated with unique neuroendocrine markers and distinct histopathology of xenografts from SCLC cell lines and murine SCLC. In this study, we use integrative genomic and epigenomic analyses to explore a novel role for c-Myc and L-Myc as lineage determining factors to bridge the gap between SCLC molecular subtypes and histological classification. First, we built a novel network using the Bayesian estimation from combined mRNA expression profile datasets for a total of 135 primary SCLC tumors. This revealed distinct transcriptional networks for c-Myc and L-Myc; wherein L-Myc was enriched for neuronal pathways and c-Myc for Notch signaling and epithelial-to-mesenchymal transition. The assay for transposase accessible-chromatin profiling of 3 representative cell lines for each c-Myc and L-Myc, revealed enrichment of biological processes involved in neuronal development for L-Myc expressing cell lines and active Notch signaling in c-Myc expressing cell lines. Together, these analyses implied that c-Myc and L-Myc govern distinct transcriptional programs to impart respective transcriptional networks associated with features unique to SCLC molecular subtypes. Next, we genetically engineered c-Myc amplified SCLC to exchange c-Myc with L-Myc and found L-Myc regulates neuronal associated pathways but was insufficient to induce lineage switch, however; c-Myc was required for the maintenance of NeuroD1-driven lineage state. In contrast, exogenous expression of c-Myc in classical-ASCL1-positive SCLC revealed incompatibility of c-Myc expression in this subtype, and led to suppression of neuronal associated pathways, trans-differentiation to NeuroD1-SCLC accompanied by variant histopathological features.
Pharmacological inhibition of neuroendocrine-low associated Notch signaling and its target RE-1 silencing transcription factor (REST), revealed c-Myc-induced suppression of ASCL1 is not mediated by Notch signaling but rather by direct activation of REST expression. Collectively, our findings reveal a previously undescribed role for historically defined general oncogenes, c-Myc and L-Myc, in regulating lineage plasticity across SCLC molecular subtypes as well as histological classes.
Citation Format: Ayushi S. Patel, Seungyeul Yoo, Ranran Kong, Takashi Sato, Maya Fridrikh, German Nudelman, Charles A. Powell, Jun Zhu, Hideo Watanabe. Myc family members differentially regulate lineage plasticity in small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1295.