Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression

Abstract

Tumour-repopulating cells (TRCs) are a self-renewing, tumorigenic subpopulation of cancer cells critical in cancer progression. However, the underlying mechanisms of how TRCs maintain their self-renewing capability remain elusive. Here we show that relatively undifferentiated melanoma TRCs exhibit plasticity in Cdc42-mediated mechanical stiffening, histone 3 lysine residue 9 (H3K9) methylation, Sox2 expression and self-renewal capability. In contrast to differentiated melanoma cells, TRCs have a low level of H3K9 methylation that is unresponsive to matrix stiffness or applied forces. Silencing H3K9 methyltransferase G9a or SUV39h1 elevates the self-renewal capability of differentiated melanoma cells in a Sox2-dependent manner. Mechanistically, H3K9 methylation at the Sox2 promoter region inhibits Sox2 expression that is essential in maintaining self-renewal and tumorigenicity of TRCs both in vitro and in vivo. Taken together, our data suggest that 3D soft-fibrin-matrix-mediated cell softening, H3K9 demethylation and Sox2 gene expression are essential in regulating TRC self-renewal.

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

“…Previous studies have shown that metastasis appears to occur primarily in soft organs/tissues in cancer patients [34,35] and cancer cells from metastatic tumors were softer [36]. Although the underlying mechanisms are not fully understood, we have recently proposed a putative model, in which cell and tissue softness contributes to the tropism of cancer metastasis and recurrence [17]. Here, we provide further evidence that the soft feature of the cell renders TRCs to effectively take up the MPs.…”

“…More significantly, when these spheroids were digested into single cells by dispase, as few as 10 cells were able to grow tumors in immunocompetent mice. We thus functionally defined these soft 3D fibrin gel-cultured cells as tumor-repopulating cells (TRCs) [16,17]. These TRCs can be easily isolated from the spheroids formed in the soft fibrin gels.…”

STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells

“…We found that IFN-β-treated B16 and A375 TRCs were more resistant to methatrexate and paclitaxol than control TRCs ( Figure 2F). Nottumorigenesis, metastasis, and drug resistance (13)(14)(15). Whether SCLCCs can more readily enter dormancy by immune cues also remains unclear.…”

“…Despite the importance of stem cell-like tumor cells in tumor initiation, progression, metastasis, and drug resistance, a hindrance lies in that this population belongs to a minor subpopulation and that the number insufficiency restricts extensive mechanistic study on stem cell-like tumor cells. To overcome this limitation, we previously established a mechanics-based 3D soft fibrin gel culture system to select and amplify TRCs (13)(14)(15)(16). When we seeded CD133…”

Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway

“…[1][2][3][4] Stem cell-like cancer cells that can repopulate tumors tumor-repopulating cells (TRC) [5][6][7] are a self-renewing, highly tumorigenic subpopulation of cancer cells and play crucial roles in the initiation, promotion and progression of tumorigenesis. Recent studies have highlighted the critical role of TRCs in regulating the effect of immune cells on tumors.…”