肿瘤再生细胞（TRCs）是一种用生物力学方法筛选出来的肿瘤细胞亚群，具有成瘤性强、耐药性强、转移性强等特点。在TRCs形成过程中，力学微环境可以调控细胞组蛋白甲基化及干性基因表达，但力学信号如何传递到细胞核并影响组蛋白甲基化及基因表达目前还不清楚。申请人前期发表的工作发现，细胞外力学信号能经由整合素、细胞质骨架直接传递到细胞核内，拉伸染色质直接诱导基因表达。异染色质蛋白1（HP1）、障碍自整合蛋白（BAF）等核蛋白在其中发挥了力学感受器的作用。据此推测，细胞核内力学感受器在TRCs形成过程中可能起到决定性作用。本项目拟在TRCs形成过程中抑制其细胞核力学感受器，比较被抑制细胞与正常TRCs生长情况、成瘤能力及耐药性的异同，检测两者组蛋白甲基化及干性基因表达水平，探索细胞核力学感受器在TRCs形成过程中的作用，阐明TRCs形成中的力学生物学机理，为肿瘤治疗提供新的理论依据。

Tumour-repopulating cells (TRCs) are a subpopulation of tumor cells selected by biomechanical method, which have satisfactory characteristics with tumorigenicity, drug resistance and metastasis. During the formation of TRCs, the mechanical microenvironment can regulate cellular histone methylation and stemness. However, it is still elusive how mechanical signals propagate to nucleus then affect histone methylation and gene expression. In the previous work published by the applicant, it was found that extracellular mechanical signals, transmitted to the nucleus via integrin and cytoplasmic skeleton, could stretch chromatin and induce gene expression directly. Nuclear proteins such as heterochromatin protein 1 (HP1) and barrier-to-autointegration factor (BAF) acted as mechano-biosensors. Thus, we speculate that the mechano-biosensors in nucleus may play a critical role in TRCs formation. This project aims to inhibit the nuclear mechano-biosensors during TRCs formation, compare the growth, tumorigenicity and drug resistance between the inhibited tumor cells and normal TRCs, as well as histone methylation and stemness related gene expression. This project intends to explore the role of nuclear mechano-biosensors and elucidate the mechanical mechanism in TRCs formation, which will provide a new theoretical basis for tumor therapy.