Abstract
Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which cells within a tumor can sustain the long-term cancer growth. Numerous cancer types exhibit high inter- and intratumor heterogeneity of H1.0, with H1.0 levels correlating with tumor differentiation status, patient survival, and, at the single-cell level, cancer stem cell markers. Silencing of H1.0 promotes maintenance of self-renewing cells by inducing derepression of megabase-sized gene domains harboring downstream effectors of oncogenic pathways. Self-renewing epigenetic states are not stable, and reexpression of H1.0 in subsets of tumor cells establishes transcriptional programs that restrict cancer cells' long-term proliferative potential and drive their differentiation. Our results uncover epigenetic determinants of tumor-maintaining cells.
Highlights
Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential
We have shown by gene expression analysis that self-renewing tumor cells, which are marked by the surface antigen SSEA1 (SSEA1+ cells), are molecularly distinct from their SSEA1- differentiated progeny (Fig. S1A) [15]
Cell-to-cell signaling such as Wnt, Tgfβ and Notch pathways, have been shown to play critical roles in driving functional heterogeneity within tumors [38], but very little is known about the downstream, cell-intrinsic mechanisms that translate signaling into differential cell function
Summary
Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Phenotypic and functional heterogeneity can be mapped to distinct differentiation states [5,6,7], suggesting that epigenetic changes occurring during tumor growth may establish cellular hierarchies within the neoplastic mass, thereby affecting the long-term proliferative potential of cancer cells. In line with this notion, individual tumors have been shown to contain distinct subpopulations of undifferentiated, self-renewing cells, and more differentiated cells, which only have limited proliferative ability [8, 9]. The functional differences that distinguish SSEA1+ and SSEA1- tumor cells – undifferentiated phenotype, long-term self-renewal ability and high tumorigenic potential versus differentiated phenotype, limited proliferative potential and low tumorigenicity - are general features associated with differentiation hierarchies in many cancer types, regardless of the tissue of origin
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