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Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity

Author

Listed:
  • Xue Zhang

    (The Wistar Institute
    Ludwig Institute for Cancer Research
    Johns Hopkins University School of Medicine)

  • Shishir M. Pant

    (Laboratory of Systems Pharmacology, Harvard Medical School
    Harvard Medical School
    Harvard Medical School)

  • Cecily C. Ritch

    (Laboratory of Systems Pharmacology, Harvard Medical School
    Harvard Medical School
    Brigham and Women’s Hospital, 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
    Ludwig Institute for Cancer Research)

  • Rebekah Brooks

    (The Wistar Institute
    Ludwig Institute for Cancer Research)

  • Patricia Brafford

    (The Wistar Institute
    Ludwig Institute for Cancer Research)

  • Adam J. Wolpaw

    (The Wistar Institute
    Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia)

  • 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
    Harvard Medical School
    Harvard Medical School)

  • Sandro Santagata

    (Laboratory of Systems Pharmacology, Harvard Medical School
    Harvard Medical School
    Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School)

  • Chi V. Dang

    (The Wistar Institute
    Ludwig Institute for Cancer Research
    Johns Hopkins University School of Medicine
    Johns Hopkins University)

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.

Suggested 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 , 2024. "Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44778-2
    DOI: 10.1038/s41467-024-44778-2
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