Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21–CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21–CCR7 axis correlated with KAT5 expression and HMGCS1^K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.

胶质母细胞瘤是最致命的原发性脑肿瘤，胶质母细胞瘤干细胞（GSC）位于细胞层次结构的顶层。GSC 通常位于血管周围的微环境中，在那里它们接收来自内皮细胞的维持信号，但异质内皮细胞群的作用仍未解决。在这里，我们发现淋巴管内皮样细胞（LEC）虽然以前在脑实质中未被识别，但存在于胶质母细胞瘤中，并通过 CCL21 分泌促进 CCR7 阳性 GSC 的生长。LEC 和 GSC 之间 CCL21-CCR7 旁分泌通讯的破坏抑制了 GSC 的增殖和生长。LEC 衍生的 CCL21 诱导 GSC 中 KAT5 介导的 HMGCS1 在 K273 上的乙酰化，以增强 HMGCS1 蛋白稳定性。HMGCS1 促进 GSC 中胆固醇的合成，有利于肿瘤生长。胶质母细胞瘤标本中CCL21-CCR7 轴的表达与 KAT5 表达和 HMGCS1 ^{K273乙酰化相关，从而告知患者预后。}总的来说，胶质母细胞瘤含有以前未被识别的 LEC，它们促进内皮细胞和肿瘤细胞之间的分子串扰，提供潜在的替代治疗策略。