Journal article
Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism
Nature cancer, Vol.5(1), pp.147-166
01/01/2024
DOI: 10.1038/s43018-023-00658-0
PMID: 38172338
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.
Rich and colleagues identify that lymphatic endothelial-like cells in glioblastoma drive the growth of cancer stem cells via CCL21-CCR7 signaling, inducing KAT5 to acetylate HMGSC1, which enhances its protein stability and cholesterol synthesis.
Details
- Title: Subtitle
- Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism
- Creators
- Linjie Zhao - UPMC Hillman Cancer CenterZhixin Qiu - University of Pittsburgh Medical CenterZhengnan Yang - Sichuan UniversityLian Xu - Sichuan UniversityThomas M. Pearce - University of PittsburghQiulian Wu - University of Pittsburgh Medical CenterKailin Yang - Cleveland ClinicFulong Li - University of California San Diego Medical CenterOlivier Saulnier - Hospital for Sick ChildrenFan Fei - University of Electronic Science and Technology of ChinaHuaxu Yu - University of British ColumbiaRyan C. Gimple - Case Western Reserve UniversityVenkateshwari Varadharajan - Cleveland Clinic Lerner College of MedicineJuxiu Liu - Sichuan UniversityLiam D. Hendrikse - Hospital for Sick ChildrenVernon Fong - Hospital for Sick ChildrenWei Wang - Huzhou Women and Children's HospitalJiao Zhang - Hospital for Sick ChildrenDeguan Lv - University of Pittsburgh Medical CenterDerrick Lee - UPMC Hillman Cancer CenterBrandon M. Lehrich - University of Pittsburgh Medical CenterChunyu Jin - University of California, San DiegoLiang Ouyang - Sichuan UniversityDeobrat Dixit - University of California, San DiegoHaoxing Wu - Sichuan UniversityXiang Wang - Sichuan UniversityAndrew E. Sloan - Case Western Reserve UniversityXiuxing Wang - Nanjing Medical UniversityTao Huan - University of British ColumbiaJ. Mark Brown - Cleveland ClinicSteven A. Goldman - University of Rochester Medical CenterMichael D. Taylor - Hospital for Sick ChildrenShengtao Zhou - Sichuan UniversityJeremy N. Rich - University of Pittsburgh Medical Center
- Resource Type
- Journal article
- Publication Details
- Nature cancer, Vol.5(1), pp.147-166
- Publisher
- NATURE PORTFOLIO
- DOI
- 10.1038/s43018-023-00658-0
- PMID
- 38172338
- ISSN
- 2662-1347
- eISSN
- 2662-1347
- Number of pages
- 36
- Grant note
- 82273255; 81822034; 81821002; 82273473; 82072779 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Shanghai Municipal Health Commission 2022YFA1106600; 2017YFA0106800; 2018YFA0109200 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) 2022YQ062 / Sichuan Science-Technology International Cooperation Project 22ZYZYTS0070; 2019YFH0144 / National Key Research and Development Program of China; National Key Research & Development Program of China T32 CA094186; F30 CA217065; F31 CA243296; R35 CA197718; R01 CA238662; R01 CA268634; R01 NS103434; R01NS106155; R01CA159859; R01CA255369 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
- Language
- English
- Date published
- 01/01/2024
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696712102771
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