Abstract：
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 HMGCS1K273 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.
摘要：
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）位于细胞层次结构之上。GSC通常位于血管周围的小生境中，它们从内皮细胞接收维持信号，但异质内皮细胞群的作用仍未解决.这里,我们显示淋巴内皮样细胞（LECs），虽然以前在脑实质中没有被识别，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旁分泌通讯的中断抑制了GSC的增殖和生长。LEC衍生的CCL21诱导KAT5介导的GSC中K273上的HMGCS1乙酰化以增强HMGCS1蛋白稳定性。HMGCS1促进GSCs中胆固醇合成,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HMGCS1K273乙酰化相关,告知患者结果。总的来说，胶质母细胞瘤含有以前未被识别的LEC，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。
