Summary: Reactivation of an ancient endogenous retrovirus, HML-2 (a subtype of HERV-K), appears to drive a more aggressive, treatment-resistant form of glioblastoma by promoting a stem-cell–like state in tumor cells.
A multidisciplinary research team found that HML-2 influences tumor cell programming through the transcription factor OCT4, linking viral reactivation to the maintenance of cancer stem cells and suggesting new therapeutic targets for this deadly brain tumor.
Key Facts:
- HML-2 is a human endogenous retrovirus integrated into the genome millions of years ago; when reactivated, it can contribute to glioblastoma biology.
- HML-2 promotes a stem-cell–like phenotype in glioma cells by activating OCT4, which supports tumor aggressiveness and resistance to therapy.
- In experimental models, antiretroviral treatment reduced HML-2 activity and decreased markers of tumor stem cells, highlighting potential avenues for therapy.
Source: Sylvester Comprehensive Cancer Center
Background
Glioblastoma is an aggressive primary brain tumor with a median survival around 14 months after diagnosis. Tumor behavior varies, however, and some glioblastomas are especially treatment-resistant. New research from the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine implicates reactivation of an ancient endogenous retrovirus, HML-2 (HERV-K), in promoting a more aggressive glioblastoma phenotype.
“Our laboratory found that an evolutionarily dormant retrovirus—HML-2, a subtype of HERV-K—contributes to brain tumor biology when it becomes reactivated,” said neurosurgeon Dr. Ashish Shah, principal investigator at Sylvester’s Brain Tumor Initiative and first author on the study published in the Journal of Clinical Investigation.
Cancer stem cells are a small but critical subpopulation within tumors that drive initiation, progression, and recurrence. They are linked to resistance to conventional therapies. The investigators showed that HML-2 activity helps define and maintain this cancer stem-cell state in high-grade gliomas.
Mechanism and experimental findings
The research team, which included scientists from Sylvester, Georgetown University, and the National Institutes of Health, used patient-derived glioblastoma samples, single-cell RNA sequencing, CRISPR interference, and mouse models to map how HML-2 affects tumor biology. They found elevated HML-2 expression in neural progenitor–like tumor cells—cells that contribute to tumor plasticity and stemness.
Molecular studies revealed that HML-2 activates the embryonic stem-cell transcription factor OCT4. OCT4 binds to an HML-2–specific long terminal repeat (LTR5Hs), driving programs associated with pluripotency and changing three-dimensional cellular morphology in neural progenitor–derived astroglia. These changes support a stem-like niche within the tumor microenvironment and promote tumorigenesis.
Notably, some glioblastoma cells showed formation of immature retroviral particles and extracellular reverse transcriptase activity. In laboratory experiments, inhibiting HML-2—either genetically via CRISPR interference or pharmacologically with antiretroviral agents—reduced reverse transcriptase activity, decreased tumor cell viability, and lowered pluripotency markers, indicating loss of the stem-cell phenotype.
Implications for therapy
Because glioblastoma stem cells are thought to underlie recurrence and treatment resistance, targeting HML-2 offers a promising strategy to disrupt the stem-cell niche and sensitize tumors to conventional treatments. The observed effects of antiretroviral drugs in experimental systems point to potential translational approaches that merit further investigation in preclinical and clinical studies.
“Targeting the glioblastoma stem cell niche represents an attractive approach to prevent stem-cell–driven tumor recurrence and overcome treatment resistance,” said Dr. Shah, who directs clinical trials and translational research in the Section of Virology and Immunotherapy at Sylvester’s Brain Tumor Initiative.
About HERVs and HML-2
Human endogenous retroviruses (HERVs) are remnants of ancient viral infections that now occupy roughly 8% of the human genome. Most HERV sequences are normally silenced and cannot produce infectious virus, but certain elements, including the relatively recent HERV-K (HML-2), can be transcriptionally reactivated in some cancers and influence cellular behavior.
Contributors and disclosures
Authors from the University of Miami include Dr. Ashish Shah (first author), Vaidya Govindarajan, Dr. Jay Chandar, Deepa Seetharam, PhD, Jelisah Desgraves, Dr. Michael Ivan, and Dr. Ricardo Komotar. The full author list and affiliations are reported in the original paper. Funding came in part from the Intramural Program of the National Institute of Neurological Disorders and Stroke (NIH), the Neurosurgery Research and Education Foundation, and the Florida Center for Brain Tumor Research. The authors declared no conflicts of interest.
About this brain cancer research news
Author: Sandy Van
Source: Sylvester Comprehensive Cancer Center
Contact: Sandy Van – Sylvester Comprehensive Cancer Center
Image: Image credited to Neuroscience News
Original Research: Open access. “Human Endogenous Retrovirus-K contributes to a unique stem-cell niche in glioblastoma” by Ashish Shah et al., Journal of Clinical Investigation.
Abstract (summary)
Human endogenous retroviruses (HERVs) make up nearly 8% of the human genome. While usually silenced, the most recently integrated provirus, HERV-K (HML-2), can be reactivated in certain cancers. This study reports pathological HML-2 expression in malignant gliomas—detectable in cerebrospinal fluid and tumor tissue—and associates its presence with a cancer stem cell phenotype and poorer outcomes.
Single-cell RNA sequencing identified glioblastoma cell populations with elevated HML-2 transcripts concentrated in neural progenitor–like cells that contribute to cellular plasticity. CRISPR interference experiments showed that HML-2 is required to maintain glioblastoma stemness and tumorigenic potential in neurosphere cultures and in intracranial mouse models. HML-2 was further shown to activate OCT4 through an HML-2–specific LTR (LTR5Hs), affecting embryonic stem-cell programs and 3D morphology of NPC-derived astroglia.
Some glioblastoma cells produced immature retroviral particles; blocking HML-2 expression with antiretroviral drugs reduced extracellular reverse transcriptase activity, decreased tumor viability, and lowered pluripotency. Together, these findings support a model in which HML-2 contributes fundamentally to the glioblastoma stem-cell niche and represents a potential therapeutic target to combat recurrence and treatment resistance.