Abstract A152: The oncogene MYC as a driver of circadian clock disruption and dedifferentiation in the lung: implications in early lung carcinogenesis

Abstract

Abstract Circadian rhythms (24-hour cycles) are disrupted in many human cancers, supporting cancer growth. Non-small cell lung cancers (NSCLCs) exhibit a disrupted molecular circadian clock, and associated alterations in circadian gene expression indicate a poor prognosis. However, it remains unclear how clock disruption occurs in NSCLCs and what NSCLCs gain from this disturbance. The oncogene MYC has been functionally implicated in circadian disruption in a variety of cancer cell lines. In NSCLCs, the MYC or one of its related family members is found mutated or amplified in more than 50% of the cases and its expression correlates with worse survival. BMAL1 is a non-redundant component of the circadian clock and is essential for the overall functionality of this machinery and the circadian regulation of gene expression. Using publicly available data we observed an inverse correlation between the expression of MYC and BMAL1 in LUAD. However, it is unknown if MYC drives clock disruption in the lung and whether clock disruption is functionally required for MYC oncogenic effects. Using an organoid model generated from isolated alveolar type II cells (ATII), the cell of origin lung adenocarcinoma (LUAD), the most prevalent type of NSCLC, we showed that MYC suppresses the expression of BMAL1. In parallel, MYC decreased the expression of specific ATII cell-lineage markers, suggesting the activation of a dedifferentiation program. Using an in vivo mouse model of NSCLC with MYC-inducible expression in ATII cells, we further demonstrated that MYC overexpression for 3 days induces an overall suppression of molecular clock genes, including BMAL1. We also observed that MYC increased the expression of proliferative markers such as Ki67 and promoted the loss of cell-lineage markers in ATII cells, which are early events in lung carcinogenesis. However, it is unclear if these effects are applicable to human LUAD. In human LUAD, we found that molecular subtypes that lack epithelial identity markers and are correlated with worse survival, show lower BMAL1 expression. These data corroborate with a potential implication of the molecular clock on the control of differentiation programs and tumor progression. Circadian clock pharmacological restoration in vivo, using the RORα agonist SR1078, attenuated the expression of the proliferation marker Ki67 induced by MYC in the lung, suggesting that clock disruption potentially mediates MYC oncogenic effects to some extent. Additionally, we performed CUT&TAG in a mouse lung epithelial cell line (MLE12) and identified that BMAL1 binds to the promoter of ATII identity genes (Sftpb, Abca3) and cell cycle genes (Cdk4), suggesting that the molecular clock potentially regulates lung epithelial cell identity and proliferation. Overall, our data identify MYC as a driver of circadian clock disruption in lung alveolar cells which is a potential mechanism implicated in MYC-driven proliferation and dedifferentiation in early-lung cancer. Circadian clock restoration might be a valuable tool to target MYC-amplified tumors. Citation Format: Juliana Cazarin de Menezes, Jamison Burchett, Siti Noor Ain Binti Ahmad Shahidan, Rachel E DeRollo, Brian Altman. The oncogene MYC as a driver of circadian clock disruption and dedifferentiation in the lung: implications in early lung carcinogenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A152.