Fibrin stiffness mediates dormancy of tumor-repopulating cells via a Cdc42-driven Tet2 epigenetic program

Yuying Liu, Jiadi Lv, Xiaoyu Liang, Xiaonan Yin, Le Zhang, Degao Chen, Xun Jin, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Jing Xie, Ning Wang, Bo Huang

Research output: Contribution to journalArticle

Abstract

Dormancy is recognized as a critical biological event for tumorigenic cells surviving in an extremely harsh environment. Understanding the molecular process of dormancy can unlock novel approaches to tackle cancers. We recently reported that stem-like tumor-repopulating cells (TRC) sense mechanical signals and rapidly proliferate in a 90 Pa soft fibrin matrix. Here, we show that a stiff mechanical environment induces TRC dormancy via an epigenetic program initiated by translocation of Cdc42, a cytosolic regulator of mechanotransduction, into the nucleus, where it promotes transcription of hydroxymethylating enzyme Tet2. Tet2 epigenetically activated cell-cycle–inhibiting genes p21 and p27 to induce dormancy, but also caused downregulation of integrin b3 to maintain dormancy. This stiffness-mediated dormancy was recapitulated in mouse models for both murine and primary human melanoma TRCs. These data identify an epigenetic program directed by mechanics, which drives highly tumorigenic TRCs to enter dormancy in a stiff mechanical environment. Significance: A mechanics-directed epigenetic program enables tumor-repopulating cells to enter dormancy in a stiff mechanical environment.

Original languageEnglish (US)
Pages (from-to)3926-3937
Number of pages12
JournalCancer Research
Volume78
Issue number14
DOIs
StatePublished - Jul 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Liu, Y., Lv, J., Liang, X., Yin, X., Zhang, L., Chen, D., Jin, X., Fiskesund, R., Tang, K., Ma, J., Zhang, H., Dong, W., Mo, S., Zhang, T., Cheng, F., Zhou, Y., Xie, J., Wang, N., & Huang, B. (2018). Fibrin stiffness mediates dormancy of tumor-repopulating cells via a Cdc42-driven Tet2 epigenetic program. Cancer Research, 78(14), 3926-3937. https://doi.org/10.1158/0008-5472.CAN-17-3719