Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2023-07, Vol.133 (13), p.1-18

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Electronic Journals Library - Freely accessible e-journals

Beschreibungen/Notizen

• 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.