Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity.

Nature communications 2024 Jan 20

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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 Sox10high to a Sox9high 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. © 2024. The Author(s).

Citation

Xue Zhang, Shishir M Pant, Cecily C Ritch, Hsin-Yao Tang, Hongguang Shao, Harsh Dweep, Yao-Yu Gong, Rebekah Brooks, Patricia Brafford, Adam J Wolpaw, Yool Lee, Ashani Weeraratna, Amita Sehgal, Meenhard Herlyn, Andrew Kossenkov, David Speicher, Peter K Sorger, Sandro Santagata, Chi V Dang. Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity. Nature communications. 2024 Jan 20;15(1):633