Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism

Linjie Zhao^#^{1

2}, Zhixin Qiu^#^{1

3}, Zhengnan Yang^#⁴, Lian Xu⁵, Thomas M Pearce⁶, Qiulian Wu¹, Kailin Yang⁷, FuLong Li⁸, Olivier Saulnier^{9

10}, Fan Fei¹¹, Huaxu Yu¹², Ryan C Gimple¹³, Venkateshwari Varadharajan^{14

15}, Juxiu Liu¹⁶, Liam D Hendrikse^{9

10

17}, Vernon Fong^{9

10

17}, Wei Wang¹⁸, Jiao Zhang^{9

10}, Deguan Lv¹, Derrick Lee¹, Brandon M Lehrich¹, Chunyu Jin¹⁹, Liang Ouyang²⁰, Deobrat Dixit², Haoxing Wu²¹, Xiang Wang¹⁶, Andrew E Sloan²², Xiuxing Wang²³, Tao Huan¹², J Mark Brown^{14

15}, Steven A Goldman^{24

25}, Michael D Taylor^{9

10

26}, Shengtao Zhou²⁷, Jeremy N Rich^{28

29}

Affiliations

¹ University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA.
² Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
³ Department of Anesthesiology, Zhongshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
⁴ Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, and Collaborative Innovation Center, Chengdu, China.
⁵ Department of Pathology, West China Second Hospital, Sichuan University, Chengdu, China.
⁶ Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
⁸ Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
⁹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁰ Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.
¹² Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.
¹³ Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
¹⁴ Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
¹⁵ Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁶ Division of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
¹⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department of Gynecology, Huzhou Maternity & Child Health Care Hospital, Huzhou, China.
¹⁹ Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
²⁰ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China.
²¹ Huaxi MR Research Center, Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
²² Department of Neurosurgery, Case Western Reserve University, Cleveland, OH, USA.
²³ School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
²⁴ University of Rochester Medical Center, Rochester, NY, USA.
²⁵ University of Copenhagen, Copenhagen, Denmark.
²⁶ Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁷ Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, and Collaborative Innovation Center, Chengdu, China. taotaovip2005@163.com.
²⁸ University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. drjeremyrich@gmail.com.
²⁹ Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. drjeremyrich@gmail.com.

^# Contributed equally.

PMID: 38172338
DOI: 10.1038/s43018-023-00658-0

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism

Linjie Zhao et al. Nat Cancer. 2024 Jan.

. 2024 Jan;5(1):147-166.

doi: 10.1038/s43018-023-00658-0. Epub 2024 Jan 3.

Authors

Affiliations

¹ University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA.
² Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
³ Department of Anesthesiology, Zhongshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
⁴ Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, and Collaborative Innovation Center, Chengdu, China.
⁵ Department of Pathology, West China Second Hospital, Sichuan University, Chengdu, China.
⁶ Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
⁸ Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
⁹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁰ Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.
¹² Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.
¹³ Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
¹⁴ Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
¹⁵ Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁶ Division of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
¹⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department of Gynecology, Huzhou Maternity & Child Health Care Hospital, Huzhou, China.
¹⁹ Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
²⁰ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China.
²¹ Huaxi MR Research Center, Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
²² Department of Neurosurgery, Case Western Reserve University, Cleveland, OH, USA.
²³ School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
²⁴ University of Rochester Medical Center, Rochester, NY, USA.
²⁵ University of Copenhagen, Copenhagen, Denmark.
²⁶ Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁷ Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, and Collaborative Innovation Center, Chengdu, China. taotaovip2005@163.com.
²⁸ University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. drjeremyrich@gmail.com.
²⁹ Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. drjeremyrich@gmail.com.

^# Contributed equally.

PMID: 38172338
DOI: 10.1038/s43018-023-00658-0

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 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.

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References

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Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism

Affiliations

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism

Authors

Affiliations

Abstract

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous