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

Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity

Nat Commun. 2024 Jan 20;15(1):633. doi: 10.1038/s41467-024-44778-2.

Authors

Xue Zhang^{1

2

3}, Shishir M Pant^{4

5

6}, Cecily C Ritch^{4

5

7}, Hsin-Yao Tang⁸, Hongguang Shao⁸, Harsh Dweep⁸, Yao-Yu Gong^{8

9}, Rebekah Brooks^{8

9}, Patricia Brafford^{8

9}, Adam J Wolpaw^{8

10

11}, Yool Lee¹², Ashani Weeraratna¹³, Amita Sehgal¹⁴, Meenhard Herlyn⁸, Andrew Kossenkov⁸, David Speicher⁸, Peter K Sorger^{4

5

6}, Sandro Santagata^{4

5

6

7}, Chi V Dang^{15

16

17

18}

Affiliations

¹ The Wistar Institute, Philadelphia, PA, USA. xzhan325@jh.edu.
² Ludwig Institute for Cancer Research, New York, NY, USA. xzhan325@jh.edu.
³ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. xzhan325@jh.edu.
⁴ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
⁵ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
⁶ Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ The Wistar Institute, Philadelphia, PA, USA.
⁹ Ludwig Institute for Cancer Research, New York, NY, USA.
¹⁰ Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Center for Childhood Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA.
¹³ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Howard Hughes Medical Institute, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ The Wistar Institute, Philadelphia, PA, USA. cvdang@jhmi.edu.
¹⁶ Ludwig Institute for Cancer Research, New York, NY, USA. cvdang@jhmi.edu.
¹⁷ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. cvdang@jhmi.edu.
¹⁸ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. cvdang@jhmi.edu.

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 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.

MeSH terms

ARNTL Transcription Factors / genetics
ARNTL Transcription Factors / metabolism
Animals
Carcinogenesis / genetics
Circadian Clocks* / genetics
Circadian Rhythm / genetics
Humans
Melanoma* / genetics
Mice

Substances

ARNTL Transcription Factors
Bmal1 protein, mouse

Abstract

MeSH terms

Substances

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