Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM is limited to the resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrated clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Edge cells show a higher capacity for infiltrative growth, while core cells demonstrate greater therapy resistance. Investigation of intercellular signaling between these two cell populations uncovered the paracrine crosstalk from tumor core that provokes malignancy and therapy resistance of edge cells. These phenotypic alterations were initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence. Comparison of edge and core regions within human glioblastoma tumors

胶质母细胞瘤（GBM）的瘤内空间异质性可促进其治疗抵抗。然而，当前学界对GBM的认知仅局限于可切除的肿瘤核心病灶，而肿瘤复发的种子细胞实则存在于不可切除的肿瘤边缘区域。本研究将GBM瘤体划分为核心与边缘区域，证实该分区模式与临床相关手术后遗症存在关联。我们构建了GBM边缘及核心区域来源的细胞模型，二者可通过细胞自主方式保留各自的空间身份特征。边缘区域细胞展现出更强的浸润生长能力，而核心区域细胞则表现出更高的治疗抵抗性。对这两类细胞群之间的细胞间信号传导进行研究后，我们发现肿瘤核心细胞可通过旁分泌串扰，诱发边缘细胞的恶性表型与治疗抵抗。上述表型改变由GBM核心细胞中的组蛋白去乙酰化酶1（HDAC1）启动，随后核心细胞通过分泌可溶性CD109蛋白对边缘细胞产生影响。本研究数据揭示了GBM不同区域肿瘤细胞间的通讯在肿瘤复发过程中的关键作用。本研究还对人源胶质母细胞瘤瘤体内的边缘与核心区域展开了对比分析。