Cell State Dependent Effects of Bmal1 on Melanoma Immunity and Tumorigenicity

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jan 20

PMID 38245503

Authors

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

Affiliations

Soon will be listed here.

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 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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References

Allada R, Bass J . Circadian Mechanisms in Medicine. N Engl J Med. 2021; 384(6):550-561. PMC: 8108270. DOI: 10.1056/NEJMra1802337. View

Bass J, Lazar M . Circadian time signatures of fitness and disease. Science. 2016; 354(6315):994-999. DOI: 10.1126/science.aah4965. View

Panda S . Circadian physiology of metabolism. Science. 2016; 354(6315):1008-1015. PMC: 7261592. DOI: 10.1126/science.aah4967. View

Kondratov R, Kondratova A, Gorbacheva V, Vykhovanets O, Antoch M . Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev. 2006; 20(14):1868-73. PMC: 1522083. DOI: 10.1101/gad.1432206. View

Yuan X, Zhu C, Wang M, Mo F, Du W, Ma X . Night Shift Work Increases the Risks of Multiple Primary Cancers in Women: A Systematic Review and Meta-analysis of 61 Articles. Cancer Epidemiol Biomarkers Prev. 2018; 27(1):25-40. DOI: 10.1158/1055-9965.EPI-17-0221. View

Papagiannakopoulos T, Bauer M, Davidson S, Heimann M, Subbaraj L, Bhutkar A . Circadian Rhythm Disruption Promotes Lung Tumorigenesis. Cell Metab. 2016; 24(2):324-31. PMC: 5367626. DOI: 10.1016/j.cmet.2016.07.001. View

Ye Y, Xiang Y, Ozguc F, Kim Y, Liu C, Park P . The Genomic Landscape and Pharmacogenomic Interactions of Clock Genes in Cancer Chronotherapy. Cell Syst. 2018; 6(3):314-328.e2. PMC: 6056007. DOI: 10.1016/j.cels.2018.01.013. View

Anafi R, Francey L, Hogenesch J, Kim J . CYCLOPS reveals human transcriptional rhythms in health and disease. Proc Natl Acad Sci U S A. 2017; 114(20):5312-5317. PMC: 5441789. DOI: 10.1073/pnas.1619320114. View

Kettner N, Voicu H, Finegold M, Coarfa C, Sreekumar A, Putluri N . Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis. Cancer Cell. 2016; 30(6):909-924. PMC: 5695235. DOI: 10.1016/j.ccell.2016.10.007. View

10.

Lee S, Donehower L, Herron A, Moore D, Fu L . Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. PLoS One. 2010; 5(6):e10995. PMC: 2881876. DOI: 10.1371/journal.pone.0010995. View

11.

Cheung M, Briscoe J . Neural crest development is regulated by the transcription factor Sox9. Development. 2003; 130(23):5681-93. DOI: 10.1242/dev.00808. View

12.

Rambow F, Marine J, Goding C . Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities. Genes Dev. 2019; 33(19-20):1295-1318. PMC: 6771388. DOI: 10.1101/gad.329771.119. View

13.

Tsoi J, Robert L, Paraiso K, Galvan C, Sheu K, Lay J . Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress. Cancer Cell. 2018; 33(5):890-904.e5. PMC: 5953834. DOI: 10.1016/j.ccell.2018.03.017. View

14.

Shaffer S, Dunagin M, Torborg S, Torre E, Emert B, Krepler C . Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature. 2017; 546(7658):431-435. PMC: 5542814. DOI: 10.1038/nature22794. View

15.

Torre E, Arai E, Bayatpour S, Jiang C, Beck L, Emert B . Genetic screening for single-cell variability modulators driving therapy resistance. Nat Genet. 2021; 53(1):76-85. PMC: 7796998. DOI: 10.1038/s41588-020-00749-z. View

16.

Riesenberg S, Groetchen A, Siddaway R, Bald T, Reinhardt J, Smorra D . MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment. Nat Commun. 2015; 6:8755. PMC: 4659938. DOI: 10.1038/ncomms9755. View

17.

Cheng P, Shakhova O, Widmer D, Eichhoff O, Zingg D, Frommel S . Methylation-dependent SOX9 expression mediates invasion in human melanoma cells and is a negative prognostic factor in advanced melanoma. Genome Biol. 2015; 16:42. PMC: 4378455. DOI: 10.1186/s13059-015-0594-4. View

18.

Kumar S, Yu H, Edwards R, Chen L, Kazianis S, Brafford P . Mutant V600E BRAF increases hypoxia inducible factor-1alpha expression in melanoma. Cancer Res. 2007; 67(7):3177-84. DOI: 10.1158/0008-5472.CAN-06-3312. View

19.

Meeth K, Wang J, Micevic G, Damsky W, Bosenberg M . The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterations. Pigment Cell Melanoma Res. 2016; 29(5):590-7. PMC: 5331933. DOI: 10.1111/pcmr.12498. View

20.

Moreno B, Zaretsky J, Garcia-Diaz A, Tsoi J, Parisi G, Robert L . Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells. Cancer Immunol Res. 2016; 4(10):845-857. PMC: 5050168. DOI: 10.1158/2326-6066.CIR-16-0060. View