Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.
Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.
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DOI：
10.1038/s43018-023-00658-0
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发表时间：
2024-01
期刊：
影响因子：
22.7
通讯作者：
Linjie Zhao;Zhixin Qiu;Zhengnan Yang;Lian Xu;Thomas M Pearce;Qiulian Wu;Kailin Yang;FuLong Li;Olivier Saulnier;Fan Fei;Huaxu Yu;Ryan C. Gimple;Venkateshwari Varadharajan;Juxiu Liu;Liam D Hendrikse;Vernon Fong;Wei Wang;Jiao Zhang;Deguan Lv;Derrick Lee;Brandon M Lehrich;Chunyu Jin;Ouyang Liang;D. Dixit;Haoxing Wu;Xiang Wang;Andrew E. Sloan;Xiuxing Wang;Tao Huan;J. Mark Brown;Steven A. Goldman;Michael D Taylor;Shengtao Zhou;Jeremy N. Rich
中科院分区：
文献类型：
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作者：
Linjie Zhao;Zhixin Qiu;Zhengnan Yang;Lian Xu;Thomas M Pearce;Qiulian Wu;Kailin Yang;FuLong Li;Olivier Saulnier;Fan Fei;Huaxu Yu;Ryan C. Gimple;Venkateshwari Varadharajan;Juxiu Liu;Liam D Hendrikse;Vernon Fong;Wei Wang;Jiao Zhang;Deguan Lv;Derrick Lee;Brandon M Lehrich;Chunyu Jin;Ouyang Liang;D. Dixit;Haoxing Wu;Xiang Wang;Andrew E. Sloan;Xiuxing Wang;Tao Huan;J. Mark Brown;Steven A. Goldman;Michael D Taylor;Shengtao Zhou;Jeremy N. Rich
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）位于细胞层级的顶部。GSC通常驻留在血管周围的小生境中，在那里它们从内皮细胞接收维持信号，但是异质性内皮细胞群体的作用仍然没有得到解决。在这里，我们表明，淋巴管内皮样细胞（LEC），而以前未被识别的脑实质中，存在于胶质母细胞瘤和促进生长的CCR 7阳性GSC通过CCL 21分泌。干扰LEC和GSC之间的CCL 21-CCR 7旁分泌通讯抑制GSC增殖和生长。LEC衍生的CCL 21诱导GSC中K273上KAT 5介导的HMGCS 1乙酰化，以增强HMGCS 1蛋白的稳定性。HMGCS 1促进GSC中胆固醇的合成，有利于肿瘤的生长。胶质母细胞瘤标本中CCL 21-CCR 7轴的表达与KAT 5表达和HMGCS 1 K273乙酰化相关，为患者预后提供信息。总的来说，胶质母细胞瘤含有以前未被识别的LEC，其促进内皮细胞和肿瘤细胞之间的分子串扰，提供了潜在的替代治疗策略。
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 HMGCS1K273acetylation 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.