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

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 macro-H2A 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-beta 2 and p38 alpha/0 pathways up-regulate macroH2A expression and that macroH2A variant overexpres-sion 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.

Automated summary

MacroH2A variants play a crucial role in inhibiting metastasis in cancer. Dormant disseminated cancer cells (DCCs) were found to have increased levels of macroH2A variants compared to proliferating primary or metastatic lesions in head and neck squamous cell carcinoma. The study further reveals that transforming growth factor-beta 2 and p38 alpha/0 pathways up-regulate macroH2A expression, leading to DCC dormancy and suppression of metastasis in vivo.