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MacroH2A impedes metastatic growth by enforcing a discrete dormancy program in disseminated cancer cells

Authors :
Dan Sun
Deepak K. Singh
Saul Carcamo
Dan Filipescu
Bassem Khalil
Xin Huang
Brett A. Miles
William Westra
Karl Christoph Sproll
Dan Hasson
Emily Bernstein
Julio A. Aguirre-Ghiso
Source :
Science advances. 8(48)
Publication Year :
2022

Abstract

MacroH2A variants have been linked to inhibition of metastasis through incompletely understood mechanisms. Here, we reveal that solitary dormant disseminated cancer cells (DCCs) display increased levels of macroH2A variants in head and neck squamous cell carcinoma PDX in vivo models and patient samples compared to proliferating primary or metastatic lesions. We demonstrate that dormancy-inducing transforming growth factor–β2 and p38α/β pathways up-regulate macroH2A expression and that macroH2A variant overexpression is sufficient to induce DCC dormancy and suppress metastasis in vivo. Notably, inducible expression of the macroH2A2 variant in vivo suppresses metastasis via a reversible growth arrest of DCCs. This state does not require the dormancy-regulating transcription factors DEC2 and NR2F1; instead, transcriptomic analysis reveals that macroH2A2 overexpression inhibits cell cycle and oncogenic signaling programs, while up-regulating dormancy and senescence-associated inflammatory cytokines. We conclude that the macroH2A2-enforced dormant phenotype results from tapping into transcriptional programs of both quiescence and senescence to limit metastatic outgrowth.

Details

ISSN :
23752548
Volume :
8
Issue :
48
Database :
OpenAIRE
Journal :
Science advances
Accession number :
edsair.doi.dedup.....35af999d5973fc9fcd1398ba88737098