Abstract 6710: The oncogene MYC drives circadian clock disruption and regulates cell plasticity in early lung carcinogenesis
Authors: Juliana Cazarin, Cody Naccarato, Jamison Burchett, Siti Noor Ain Binti Ahmad Shahidan, Min Yee, Michael O'Reilly, Brian J. Altman
Journal: Cancer Research (2025)

Abstract Circadian rhythms coordinate the compartmentalization of biological processes, such as cell division and metabolism, to the time of the day. Disruption of these rhythms has been implicated in lung carcinogenesis. Circadian disruption accelerates tumor growth in lung adenocarcinoma (LUAD) mouse models, suggesting an oncogenic role of disrupted rhythms. A disrupted circadian clock has been reported in human LUAD, with alterations in circadian gene expression linked to poor prognosis. However, the origins of clock disruption in LUAD and how it supports tumor growth remain unclear. The oncogene MYC has been linked to circadian disruption in cancer cells. MYC or its related family members are mutated or amplified in more than 30% of LUAD cases, with higher MYC expression associated with worse survival. An analysis of public datasets reveals an inverse correlation between MYC expression and the circadian clock gene BMAL1 in human LUAD. BMAL1, a critical component of the mammalian circadian clock, is indispensable for maintaining circadian rhythms, as its deletion leads to their complete disruption in both mice and cells. However, whether MYC directly drives clock disruption in the lung and the extent to which clock dysfunction contributes to MYC-driven carcinogenesis remain unknown. Using organoids derived from alveolar type II cells (ATII), the cell of origin for LUAD, we showed that MYC suppresses BMAL1 expression. MYC also reduced the expression of ATII cell-lineage markers, suggesting activation of a dedifferentiation program. In a LUAD mouse model, three days of MYC overexpression in ATII cells suppressed molecular clock genes, including BMAL1. This was accompanied by increased Ki67 expression, a marker of proliferation, and the loss of cell-lineage markers early events in lung carcinogenesis. Similarly, in human LUAD, molecular subtypes with reduced epithelial identity markers and poorer survival showed lower BMAL1 expression. These findings suggest a role for the circadian clock in regulating differentiation and tumor progression. Pharmacological restoration of the circadian clock in vivo using the RORα agonist SR1078 reduced MYC-induced Ki67 expression in the lung, indicating that circadian disruption mediates some of MYC’s oncogenic effects. Further analysis using CUT&amp;TAG in a mouse lung epithelial cell line revealed that BMAL1 binds to promoters of ATII identity genes (Sftpb, Abca3) and cell cycle regulators (Cdk4), suggesting that the circadian clock influences both lung epithelial cell identity and proliferation. Overall, we identify MYC as a driver of circadian clock disruption in lung alveolar cells, which may contribute to MYC-induced proliferation and dedifferentiation in early lung cancer. Restoring circadian clock function could represent a potential therapeutic strategy for targeting tumors with MYC amplification. Citation Format: Juliana Cazarin, Cody Naccarato, Jamison Burchett, Siti Noor Ain Binti Ahmad Shahidan, Min Yee, Michael O'Reilly, Brian J. Altman. The oncogene MYC drives circadian clock disruption and regulates cell plasticity in early lung carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6710.