Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity

Zhang X, Pant SM, Ritch CC, Tang H-Y, Shao H, Dweep H, Gong Y-Y, Brooks R, Brafford P, Wolpaw AJ, Lee Y, Weeraratna A, Sehgal A, Herlyn M, Kossenkov A, Speicher D, Sorger PK, Santagata S, Dang CV.

Nature Communications. 2024 Jan 20, 15(1):633. PMID: 38245503

The circadian clock regulator Bmal1 modulates tumorigenesis, but its reported effects are inconsistent. Here, we show that Bmal1 has a context-dependent role in mouse melanoma tumor growth. Loss of Bmal1 in YUMM2.1 or B16-F10 melanoma cells eliminates clock function and diminishes hypoxic gene expression and tumorigenesis, which could be rescued by ectopic expression of HIF1α in YUMM2.1 cells. By contrast, over-expressed wild-type or a transcriptionally inactive mutant Bmal1 non-canonically sequester myosin heavy chain 9 (Myh9) to increase MRTF-SRF activity and AP-1 transcriptional signature, and shift YUMM2.1 cells from a Sox10-high to a Sox9-high immune resistant, mesenchymal cell state that is found in human melanomas. Our work describes a link between Bmal1, Myh9, mouse melanoma cell plasticity, and tumor immunity. This connection may underlie cancer therapeutic resistance and underpin the link between the circadian clock, MRTF-SRF and the cytoskeleton.