骨巨细胞瘤（GCTB）是常见的原发侵袭骨肿瘤，术后复发率高达18%-50%。现有临床药物多针对骨破坏过程，而研究发现药物治疗后GCTB中的主要瘤性成分基质细胞（GCTSC）常在骨组织中残留，导致肿瘤复发。但GCTSC的细胞异质性研究仍十分有限。项目组通过单细胞RNA测序检测GCTB中的细胞异质性，并发现存在一种干细胞样GCTSC亚群，该亚群可能在GCTB的发生、发展和耐药中发挥重要作用，且该亚群的标志物之一PKMYT1可能通过与DEPDC1结合并促进其磷酸化参与干细胞样GCTSC亚群的增殖、干性维持和耐药等功能。基于这些研究结果，项目组拟进一步在体外和体内阐明干细胞样GCTSC亚群及其标志物PKMYT1在GCTB发生和发展中的作用及分子机制，明确PKMYT1对GCTB患者预后的评估作用，并探索PKMYT1抑制剂在体内对GCTB的治疗作用，为GCTB的临床治疗提供新的理论基础和药物靶点。

Giant cell tumor of bone (GCTB) is one of the most common primary invasive bone tumors, with the recurrence rate of as high as 18% - 50%. Current clinical drugs of GCTB mainly target to the process of osteoclast differentiation and bone destruction. However, studies have found that GCT stromal cells (GCTSCs), the only tumorous component in GCTB, were still remained in the newly generated bone tissues after medication treatments, leading to the recurrence of GCTB. But the study of the heterogeneity in GCTSCs is still quite limited. Thus, we performed single-cell RNA sequencing to analysis the cell heterogeneity of GCTB, and found a stem-like GCTSC subgroup. Further studies showed that the stem-like GCTSCs possibly played important roles in the occurrence, development and drug resistance of GCTB. In addition, PKMYT1, one of the markers of stem-like GCTSCs, might participate in the proliferation, stemness and drug resistance of stem-like GCTSCs by binding to DEPDC1 and promoting the phosphorylation. Next, we intend to investigate the effect and molecular mechanism of stem-like GCTSCs and its molecular marker PKMYT1 in the occurrence and development of GCTB in vitro and in vivo, and clarify the role of PKMYT1 in prognosis prediction of GCTB patients, as well as further explore the therapeutic role of PKMYT1 inhibitor in patient-derived tumor xenografts of GCTB. The present study may provide new theoretical basis and therapeutic targets for GCTB.