Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity

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 and Chi V. Dang ()
Additional contact information
Xue Zhang: The Wistar Institute
Shishir M. Pant: Laboratory of Systems Pharmacology, Harvard Medical School
Cecily C. Ritch: Laboratory of Systems Pharmacology, Harvard Medical School
Hsin-Yao Tang: The Wistar Institute
Hongguang Shao: The Wistar Institute
Harsh Dweep: The Wistar Institute
Yao-Yu Gong: The Wistar Institute
Rebekah Brooks: The Wistar Institute
Patricia Brafford: The Wistar Institute
Adam J. Wolpaw: The Wistar Institute
Yool Lee: Washington State University
Ashani Weeraratna: Johns Hopkins University
Amita Sehgal: University of Pennsylvania
Meenhard Herlyn: The Wistar Institute
Andrew Kossenkov: The Wistar Institute
David Speicher: The Wistar Institute
Peter K. Sorger: Laboratory of Systems Pharmacology, Harvard Medical School
Sandro Santagata: Laboratory of Systems Pharmacology, Harvard Medical School
Chi V. Dang: The Wistar Institute

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44778-2

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