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Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma
Ashish H. Shah, … , John D. Heiss, Avindra Nath
Ashish H. Shah, … , John D. Heiss, Avindra Nath
Published July 3, 2023
Citation Information: J Clin Invest. 2023;133(13):e167929. https://doi.org/10.1172/JCI167929.
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Research Article Virology Article has an altmetric score of 118

Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma

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Abstract

Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes. Using single-cell RNA-Seq, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor–like cells (NPC-like) that drive cellular plasticity. Using CRISPR interference, we demonstrate that HML-2 critically maintained glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models. Additionally, we demonstrate that HML-2 critically regulated embryonic stem cell programs in NPC-derived astroglia and altered their 3D cellular morphology by activating the nuclear transcription factor OCT4, which binds to an HML-2–specific long-terminal repeat (LTR5Hs). Moreover, we discovered that some glioblastoma cells formed immature retroviral virions, and inhibiting HML-2 expression with antiretroviral drugs reduced reverse transcriptase activity in the extracellular compartment, tumor viability, and pluripotency. Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem cell niche. Because persistence of glioblastoma stem cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target.

Authors

Ashish H. Shah, Sarah R. Rivas, Tara T. Doucet-O’Hare, Vaidya Govindarajan, Catherine DeMarino, Tongguang Wang, Leonel Ampie, Yong Zhang, Yeshavanth Kumar Banasavadi-Siddegowda, Stuart Walbridge, Dragan Maric, Marta Garcia-Montojo, Robert K. Suter, Myoung-Hwa Lee, Kareem A. Zaghloul, Joseph Steiner, Abdel G. Elkahloun, Jay Chandar, Deepa Seetharam, Jelisah Desgraves, Wenxue Li, Kory Johnson, Michael E. Ivan, Ricardo J. Komotar, Mark R. Gilbert, John D. Heiss, Avindra Nath

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Figure 10

HERV-K viral particles are produced in glioblastoma.

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HERV-K viral particles are produced in glioblastoma.
(A) Transmission el...
(A) Transmission electron microscopy demonstrating HML-2 virions budding from HK-transfected 293T cells. Scale bar: 100 nm. Immature virions demonstrate double-membrane morphology with envelope spikes and core capsid proteins (original magnification, ×10,000; ×20,000 [insets]). (B) Immature retroviral virions can be seen in naive glioblastoma neurospheres that share similar morphology as positive control-transfected 293T cells. Scale bar: 100 nm. (C) Using a PERT assay, reverse transcriptase levels from extracellular vesicles were significantly elevated in HML-2+ glioma neurospheres compared with HML-2–deficient glioma cell line A172 (1-way ANOVA, ****P < 0.001). (D) Sublethal dosage of abacavir (20 μM) reduced expression of pluripotency markers OCT4 and Nestin at 24 and 48 hours after exposure with qPCR (1-way ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). (E) Abacavir reduced cell viability of glioma cell lines in a dose-dependent manner (IC50 = 75.8–123.1 μM) using an XTT cell viability assay. (F) Abacavir (20 μM) reduced HERV-K ENV protein expression and OCT4 at 72 hours in patient-derived glioma neurospheres by immunofluorescence. (G) Abacavir inhibited tumor cell proliferation in a variety of cancer cell lines, with notable effect in GBM (median = –0.1550, interquartile range = –0.6601 to 0.02814). Data obtained from the DepMap. Scale bars: 50 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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