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

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.

An extramedullary bone model to study metastatic dormancy reveals a piecemeal model for metastatic reactivation.

“…The transcriptional profile of the more abundant quiescent cells also showed features of stemness, but was associated with embryonic diapause, in line with their non-proliferative state. Moreover, in line with previous evidence 16,17 , quiescent BC cells exhibited a signature indicative of activated stress signalling.…”

“…The activation of the dormant state in DTCs is associated with the mechanism of immune evasion 15 . Once activated, the dormant state of cancer cells is maintained by epigenetic changes and also by the activation of programs related to stress response, autophagy, and senescence 16,17 .…”

Unravelling the conundrum of nucleolar NR2F1 localization: A comparative analysis of NR2F1 antibody-based approachesin vitroandin vivo

“…Nonetheless, nucleolar-like NR2F1 staining detected in IF by Ab3 has previously been used to quantify NR2F1 in different tumor cells [60][61][62]64,96,97,112 . Architecture and assembly of nucleoli formed around specific chromosomal regions are highly dynamic processes.…”

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

“…47 After the initiation of migration, DCCs reach various niches and actively settle into the new organ environment to establish dormancy. [48][49][50] After signals arising from the microenvironment, DCCs can switch from their dormant state and reemerge to proliferative growth. 8 Epithelial-mesenchymal transition (EMT) is crucial gene expression program associated with cell quiescence and metastasis.…”

“…During dissemination, DCCs must overcome physical barriers by degrading the extracellular matrix (ECM) to invade the matrix, migrating along the ECM to leave the tumour and undergoing intravasation then extravasation by degrading the vascular basement membrane 47 . After the initiation of migration, DCCs reach various niches and actively settle into the new organ environment to establish dormancy 48–50 . After signals arising from the microenvironment, DCCs can switch from their dormant state and reemerge to proliferative growth 8 .…”