AI Article Synopsis

  • HERVs are remnants of ancient viruses found in our DNA, making up about 8% of the human genome, with HERV-K (HML-2) being linked to certain cancers, especially malignant gliomas.
  • The study highlights the abnormal activation of HML-2 in glioblastomas, where it promotes a cancer stem cell-like behavior associated with worse patient outcomes.
  • Researchers found that targeting HML-2 can impair tumor growth and stemness in glioblastoma, suggesting it could be a potential target for new cancer therapies due to its role in treatment resistance.

Article 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313366PMC
http://dx.doi.org/10.1172/JCI167929DOI Listing

Publication Analysis

Top Keywords

stem cell
16
human endogenous
8
cell niche
8
hml-2
8
demonstrate hml-2
8
hml-2 critically
8
glioblastoma stem
8
glioblastoma
7
stem
5
endogenous retrovirus
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!