bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.10.12.757688

Microglia-derived Small Extracellular Vesicles Promote Bone Marrow Monocyte Expansion and Recruitment in Glioblastoma.

Albuja, I.·Quiralte, M.·Panda, N.·Macaraeg, A.·Yeon, M.·Liu, Q.·Kossenkov, A.·Barnoud, T.·Bertolini, I.
View original source ↗Export metadata ↓

Abstract

Glioblastoma (GBM) remains one of the deadliest human cancers and is characterized by a profoundly immunosuppressive tumor microenvironment (TME). Although tumor-associated microglia (TAMg) promote GBM progression, their role in regulating immune cell recruitment remains poorly understood. Here, we demonstrate that TAMg-derived small extracellular vesicles (sEVs) mediate bone marrow-derived monocyte recruitment into the GBM TME. We find that these sEVs traffic to the bone marrow, where they selectively target monocytes and their progenitors. Mechanistically, sEV internalization activates MAPK signaling and inflammatory transcriptional programs, driving the differentiation and expansion of inflammatory monocytes. Together, our findings establish microglia-derived sEVs as a previously unrecognized mechanism of communication between the GBM TME and the peripheral immune system, thereby promoting the establishment of an immunosuppressive TME that drives GBM progression.

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Albuja, I., Quiralte, M., Panda, N., Macaraeg, A., Yeon, M., Liu, Q., Kossenkov, A., Barnoud, T., Bertolini, I.. 2026-10-14. Microglia-derived Small Extracellular Vesicles Promote Bone Marrow Monocyte Expansion and Recruitment in Glioblastoma.. https://doi.org/10.64898/2026.10.12.757688

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Spatial epigenomics reveals ancestry-associated regulatory states linked to aggressive prostate cancer biology

Prostate cancer (PCa) exhibits substantial biological heterogeneity, including population associated differences in tumor aggressiveness and clinical outcomes. Although socioeconomic and environmental factors contribute to these disparities, intrinsic tumor regulatory programs may also influence disease behavior. Here, we investigated whether differences in chromatin regulation contribute to distinct tumor states in Black and White men with localized PCa. We performed spatial chromatin accessibility profiling (ATAC-seq) of prostatectomy specimens from Black and White patients receiving equal healthcare access at the Center for Prostate Disease Research (USUHS) and Walter Reed National Military Medical Center. Tumors showed distinct chromatin accessibility landscapes between the two populations, with tumors from Black patients exhibiting reduced accessibility of motifs associated with the chromatin architectural regulator CTCF and enrichment of motifs linked to epithelial-mesenchymal transition and inflammatory programs. Reduced CTCF expression was independently validated by immunohistochemistry in 99 prostatectomy specimens. These findings identify population-associated differences in chromatin regulation in localized PCa and suggest that altered CTCF-associated regulation, inflammatory signaling, and epithelial plasticity may contribute to the biological heterogeneity underlying ancestry-dependent PCa disparities.

cancer biology↗
bioRxiv2026

Domain-resolved epitope mapping of B7-H3-targeting VHH-Fcs defines isoform-selective binders for antibody-drug conjugate development

The immune checkpoint molecule B7-H3 has emerged as one of the most actively pursued therapeutic targets in solid tumors, and multiple B7-H3-targeting antibody-drug conjugates have entered clinical evaluation. B7-H3 occurs as a 2Ig isoform carrying a single IgV-IgC domain pair and a predominant 4Ig isoform carrying two tandem pairs of near-identical sequence in their extracellular domains. Resolving which pair an antibody engages, or how antibodies distinguish the two isoforms, requires epitope mapping at residue level. Here we generated a panel of six B7-H3-targeting VHH-Fcs and characterized them by surface plasmon resonance, epitope binning, domain-resolved deep mutational scanning and receptor internalization, benchmarked against the clinically advanced antibodies ifinatamab, mirzotamab and vobramitamab. Most VHH-Fcs bound the membrane-proximal pair more tightly than the distal pair, and 4Ig 10- to 100-fold more tightly than 2Ig, whereas the three clinical antibodies showed no such discrimination. Displaying each domain pair independently on yeast identified the residues that account for this selectivity. Internalization varied several-fold among binders, including between VHH-Fc 620 and 636, which have near-identical footprints and comparable affinities. VHH-Fc 620 internalized most efficiently, also compared to ifinatamab, and was conjugated to exatecan through a protease-cleavable linker. The conjugate showed B7-H3-dependent cytotoxicity that scaled with B7-H3 cell surface density, though it was less potent than ifinatamab-exatecan. Affinity, epitope and internalization therefore behaved as independent characteristics rather than integrating to predict antibody-drug conjugate potency. Together, these results define the molecular basis for isoform-selective recognition of B7-H3 and identify VHH-Fc 620 as a starting point for isoform-selective targeting.

cancer biology↗
bioRxiv2026

Bioenergetic and Proteomic Profiling of ARID1A-Deficient Ovarian Clear Cell Carcinoma under Metabolic Challenge

ARID1A loss is associated with increased mitochondrial respiration in ovarian clear cell carcinoma (OCCC), but whether this phenotype is maintained under metabolic challenge remains unclear. Here, we examined mitochondrial function and electron transport chain (ETC) protein abundance in isogenic ARID1A wild-type (WT) and ARID1A-knockout (KO) OCCC cells cultured under physiological glucose, galactose, or the Complex I inhibitor IACS-010759. Across all conditions, KO cells maintained higher basal, ATP-linked, and maximal respiration, greater spare respiratory capacity, and higher coupling efficiency than WT cells, despite lower steady-state ATP levels. In human OCCC tumors, ARID1A-negative cases showed a higher bioenergetic cellular (BEC) index than ARID1A-positive cases, and high BEC was associated with poorer cancer-specific survival. Quantitative proteomics revealed a trend toward higher ETC complex abundance in KO cells, although whole-complex differences did not reach statistical significance. ARID1A loss was associated with selective increases in Complex III and V proteins, whereas metabolic challenge was associated with increases in Complex I and IV proteins. Together, these findings show that the ARID1A-associated mitochondrial phenotype persists across distinct metabolic challenges and is not explained simply by coordinated increases in ETC protein abundance. The association of mitochondrial bioenergetics with clinical outcomes further supports its relevance in human OCCC.

cancer biology↗