ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung

Abstract

Increasing evidence shows that cancer cells can disseminate from early-evolved primary lesions much earlier than the classical metastasis models predicted. It is thought that a state of early disseminated cancer cell (early DCC) dormancy can precede genetic maturation of DCCs and metastasis initiation. Here we reveal at single cell resolution a previously unrecognized role of mesenchymal-and pluripotency-like programs in coordinating early cancer cell spread and a longlived dormancy program in early DCCs. Using in vitro and in vivo models of invasion and metastasis, single cell RNA sequencing and human sample analysis, we provide unprecedented insight into how early DCC heterogeneity and plasticity control the timing of reactivation. We identify in early lesions and early DCCs the transcription factor ZFP281 as an inducer of mesenchymal-and primed pluripotency-like programs, which is absent in advanced primary tumors and overt metastasis.ZFP281 not only controls the early spread of cancer cells but also locks early DCCs in a prolonged dormancy state by preventing the acquisition of an epithelial-like proliferative program and consequent metastasis outgrowth. Thus, ZFP281-driven dormancy of early DCCs may be a ratelimiting step in metastatic progression functioning as a first barrier that DCCs must overcome to then undergo genetic maturation.

Multi-functional gene ZNF281 identified as a molecular biomarker in soft tissue regeneration and pan-cancer progression

“…First, that might be the result of environmental response to regeneration signals, which promotes cell proliferation and migration. A mesenchymal-like program as negative feedback is exerted by the environment to keep homeostasis, and then, the expression of zfp281 might be upregulated ( Kciuk et al, 2022 ; Nobre et al, 2022 ). Second, ZNF281 might promote regeneration by activating EMT-related pathways ( Hahn et al, 2013 ).…”

Multiomic single-cell lineage tracing to dissect fate-specific gene regulatory programs

“…However, Zfp281 still draws the reprogrammed cells toward an off-target, mesenchymal-like state. A role for this TF in driving broad mesenchymal expression programs, including components of the TGF-β signaling pathway, has recently been described 49 . Here, we demonstrate that the inhibition of TGF-β signaling enhances on-target marker expression while decreasing off-target gene expression.…”

“…4f (black bar), g). Several of these TFs (Zfp281, Cebpb, Gata6, Hivep3) have been previously documented to play a role in regulating mesenchymal cell identities [49][50][51][52] . Surveying the expression data, none of the off-target TFs display a similar fate-biased enrichment (Fig.…”

“…Finally, a key downstream effector of Zfp281 is TGF-β signaling 51, 60 , an Epithelial-to-Mesenchymal Transition (EMT) associated pathway 61 . Indeed, TGF-β pathway activity, as inferred using PROGENy 62 ( Methods ), increased with Zfp281 OE and decreased with Zfp281 KD, suggesting active regulation of TGF-β signaling by Zfp281.…”

Dormant cancer cells: programmed quiescence, senescence, or both?

“…Elegant studies using these techniques have already dramatically advanced our knowledge of these processes, identifying various cell-intrinsic regulators of dormancy. The processes are wide ranging and include roles for interferon signaling [127]; p38 MAP kinase pathway [128]; an axis including FGF2, the transcription factor ZFP281, and CDH11 [129]; and ECM interactions via COL17A1 [100], to name a few, highlighting just how complex and contextdependent this cell state is. Future work that continues to rely on and advance these techniques will further clarify our understanding of the heterogenous states of tumor dormancy, their relationships to quiescence and senescence, and will be invaluable in detecting dormant cancer cells, uncovering their underlying biology, and defining their role in metastatic relapse.…”