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; Chi V Dang

doi:10.1038/s41467-024-44778-2

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Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity

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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, …

Nature communications, Vol.15(1), 633

01/20/2024

DOI: https://doi.org/10.1038/s41467-024-44778-2

PMID: 38245503

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Abstract

ARNTL Transcription Factors - genetics

ARNTL Transcription Factors - metabolism

Carcinogenesis - genetics

Circadian Clocks - genetics

Circadian Rhythm - genetics

Melanoma - genetics

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 to a Sox9 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.

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Title: Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity
Creators: Xue Zhang - The Wistar Institute
Shishir M Pant - Center for Systems Biology
Cecily C Ritch - Center for Systems Biology
Hsin-Yao Tang - The Wistar Institute, Philadelphia, PA, USA
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 - Harvard University
Sandro Santagata - Center for Systems Biology
Chi V Dang - Johns Hopkins University
Publication Details: Nature communications, Vol.15(1), 633
Academic Unit: Elson S. Floyd College of Medicine
Grant note: R01 CA057341 / NCI NIH HHS U54 CA225088 / NCI NIH HHS R50 CA221838 / NCI NIH HHS R01 CA051497 / NCI NIH HHS
Identifiers: 99901130943901842
Language: English
Resource Type: Journal article