The role of human endogenous retrovirus K as a modulator of microglial function in glioblastoma

Prof. Dr. Seija Lehnardt

• B03

Dr. Michelle Vincedeau

• B03

Project Summary

Glioblastoma (GBM), representing the most common and lethal primary brain tumor in adults, is composed of
heterogeneous cell populations including glioma-associated microglia and monocyte-derived macrophages, which substantially contribute to tumor growth, immune suppression, and therapeutic resistance. Given the poor median survival of 15 months after diagnosis, it is indispensable to decipher the cellular and molecular mechanisms underlying microglia/macrophage activati on in GBM to develop new therapeutic strategies. Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the human genome. While most HERVs are inactive, certain HERVs such as HERV-K(HML-2) can be reactivated and released from cells under certain conditions, resulting in pathological states such as cancer and neuroinflammation. Considering the capability of endogenous RNA to directly activate immune receptors in the central nervous system (CNS), we hypothesize that HERV-K(HML-2) acts as a signaling molecule in glioma-associated
microglia and tumor cells, thereby contributing to GBM. We will comparatively perform single-cell RNA-seq and ATACseq in GBM pati ent tumor tissue and cerebral glioma organoids (GLICOs) and use a CASPEX approach to determine the expression and regulation of HERV-K (HML-2) and associated signaling pathways in the different GBM cell populations (Aim 1). We will determine HERV-K RNA as an endogenous signaling molecule for human microglia and investigate the role of HERV-K as a modulator of microglial function as well as the crosstalk between microglia and GBM tumor cells (Aim 2). We will assess the effects of both an altered HERV-K(HML-2) expression and extracellular HERV-K( HML-2) transcripts on GBM tumor growth using a humanized glioma slice model and GLICOs. Finally, analyzing cerebrospinal fluid and serum from GBM patients we will evaluate the potential of HERV-K(HML-2) as a biomarker for GBM (Aim 3).