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