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

Autor: Zhang X; The Wistar Institute, Philadelphia, PA, USA. xzhan325@jh.edu.; Ludwig Institute for Cancer Research, New York, NY, USA. xzhan325@jh.edu.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. xzhan325@jh.edu., Pant SM; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.; Department of Systems Biology, Harvard Medical School, Boston, MA, USA., Ritch CC; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Tang HY; The Wistar Institute, Philadelphia, PA, USA., Shao H; The Wistar Institute, Philadelphia, PA, USA., Dweep H; The Wistar Institute, Philadelphia, PA, USA., Gong YY; The Wistar Institute, Philadelphia, PA, USA.; Ludwig Institute for Cancer Research, New York, NY, USA., Brooks R; The Wistar Institute, Philadelphia, PA, USA.; Ludwig Institute for Cancer Research, New York, NY, USA., Brafford P; The Wistar Institute, Philadelphia, PA, USA.; Ludwig Institute for Cancer Research, New York, NY, USA., Wolpaw AJ; The Wistar Institute, Philadelphia, PA, USA.; Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Center for Childhood Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Lee Y; Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA., Weeraratna A; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA., Sehgal A; Howard Hughes Medical Institute, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Herlyn M; The Wistar Institute, Philadelphia, PA, USA., Kossenkov A; The Wistar Institute, Philadelphia, PA, USA., Speicher D; The Wistar Institute, Philadelphia, PA, USA., Sorger PK; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.; Department of Systems Biology, Harvard Medical School, Boston, MA, USA., Santagata S; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Dang CV; The Wistar Institute, Philadelphia, PA, USA. cvdang@jhmi.edu.; Ludwig Institute for Cancer Research, New York, NY, USA. cvdang@jhmi.edu.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. cvdang@jhmi.edu.; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. cvdang@jhmi.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jan 20; Vol. 15 (1), pp. 633. Date of Electronic Publication: 2024 Jan 20.
DOI: 10.1038/s41467-024-44778-2
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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