Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/052076

Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment

Qianghu Wang·Xin Hu·Baoli Hu·Florian Muller·Hoon Kim·Massimo Squatrito·Tom Mikkelsen·Lisa Scarpace·Floris Barthel·Yu-Hsi Lin·Nikunj Satani·Emmanuel Martinez-Ledesma·Edward Chang·Adriana Olar·Guocan Wang·Ana C. deCarvalho·Eskil Eskilsson·Siyuan Zheng·Amy B. Heimberger·Erik P. Sulman·Do-Hyun Nam·Roel G.W. Verhaak
View original source ↗Export metadata ↓

Abstract

SummaryWe leveraged IDH wild type glioblastomas and derivative neurospheres to define tumor-intrinsic transcription phenotypes. Transcriptomic multiplicity correlated with increased intratumoral heterogeneity and tumor microenvironment presence. In silico cell sorting demonstrated that M2 macrophages/microglia are the most frequent type of immune cells in the glioma microenvironment, followed by CD4 T lymphocytes and neutrophils. Hypermutation associated with CD8+ T cell enrichment. Longitudinal transcriptome analysis of 124 pairs of primary and recurrent gliomas showed expression subtype is retained in 53% of cases with no proneural to mesenchymal transition being apparent. Inference of the tumor microenvironment through gene signatures revealed a decrease in invading monocytes but a subtype dependent increase in M2 macrophages/microglia cells after disease recurrence. All expression datasets are accessible through http://recur.bioinfo.cnio.es/.\n\nSignificanceIDH wild type glioblastoma expression phenotypes have been related to tumor characteristics including genomic abnormalities and treatment response. We explored the intratumoral transcriptomic landscape, including a definition of tumor-intrinsic gene expression subtypes and how they relate to the different cellular components of the tumor immune environment. Comparison of matching primary and recurrent gliomas provided insights into the treatment-induced phenotypic tumor evolution. Proneural to mesenchymal transitions have long been suspected but were not apparent, while intratumoral heterogeneity was a predictor of subtype transition upon recurrence. Characterizing the evolving glioblastoma transcriptome en tumor microenvironment aids in designing more effective immunotherapy trials. Our study provides a comprehensive transcriptional and cellular landscape of IDH wild type GBM during treatment modulated tumor evolution.\n\nHighlightsO_LINext generation GBM-intrinsic transcriptional subtypes: proneural, classical, mesenchymal\nC_LIO_LIM2 macrophages, CD4+ T-lymphocytes and neutrophils dominate glioblastoma microenvironment\nC_LIO_LISensitivity to radiotherapy may associate with M2 macrophage presence\nC_LIO_LICD8+ T cells are enriched in hypermutated GBMs at diagnosis and recurrence\nC_LI

Source connections

Explore related subjects

Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Qianghu Wang, Xin Hu, Baoli Hu, Florian Muller, Hoon Kim, Massimo Squatrito, Tom Mikkelsen, Lisa Scarpace, Floris Barthel, Yu-Hsi Lin, Nikunj Satani, Emmanuel Martinez-Ledesma, Edward Chang, Adriana Olar, Guocan Wang, Ana C. deCarvalho, Eskil Eskilsson, Siyuan Zheng, Amy B. Heimberger, Erik P. Sulman, Do-Hyun Nam, Roel G.W. Verhaak. 2016-05-08. Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment. https://doi.org/10.1101/052076

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Species-dependent accumulation of PsaA in etioplasts points to light-independent steps in Photosystem I biogenesis

Whether Photosystem I (PSI) core subunits accumulate prior to light exposure in developing angiosperm seedlings remains unresolved, with conflicting reports across species. Here, we investigated the presence and membrane colocalization of the PSI core subunit PsaA in etioplasts of dark-grown angiosperms representing dicot and monocot species. Immunoblotting showed that PsaA accumulates in etioplasts of all three dicot species examined (pea, Arabidopsis, and runner bean), whereas in the monocot oat it was detected only after prolonged etiolation, at substantially lower levels and with an anomalously high apparent molecular weight. Blue-native PAGE analysis reveals that a fraction of PsaA co-migrates with LPOR, PsaB, FNR, and chlorophyll synthase, suggesting co-localization within a shared membrane microdomain rather than stable complex formation. The thylakoid insertase Alb3 was more abundant in dicot etioplasts, consistent with a potential role in the early integration of PsaA into the membrane. Upon illumination, pea reached PSI functionality faster than oat, with P700 oxidation detectable 30 min earlier, linking the dark accumulation of PsaA to an accelerated photosynthetic onset. These findings demonstrate light-independent accumulation of a PSI core subunit in a species-dependent manner and point to early steps in PSI biogenesis that precede full photosynthetic complex assembly. HighlightContrary to prevailing models, a Photosystem I core subunit PsaA accumulates in dark-grown angiosperm seedlings before light exposure, revealing light-independent early steps in photosynthetic complex biogenesis.

Preprint↗
bioRxiv2026

Discover Novel RNA Targeting Small Molecules by Fluorescent Aptamer Screening

Discovering small molecules targeting proteins represents a major effort in drug development. RNA, however, as a class of macromolecule that carrying out important regulatory roles in the cell as drug target, only received attention recently. Although several methods have been proposed, an easy to operate, fast and robust method is still lacking. We designed a generic florescence screening method by fusing the target RNA with a florescent aptamer (fusion RNA) and then carried out screening using high-throughput format (Fluorescent Aptamer Screening, FAS). In this work, we chose SL5 on SARS-Cov-2 5UTR as the test target. SL5 is a conserved motif across several corona virus family members whose core is not prone to mutation. We screened 9528 compounds, successfully identified four molecules (Sertraline (hydrochloride), Samuraciclib (hydrochloride), Minocycline (hydrochloride), JG-98 bind direct to the full-length SL5 at micromolar or higher affinity. The design of FAS could be easily adapted to structured RNA motifs without prior knowledge of its 3D structural information. In addition, this work showed the possibility of developing generic drugs for RNA virus by targeting the conserved viral RNA genome and paved a new way for the discovery of small molecule drugs in combating human diseases.

Preprint↗
bioRxiv2026

Mechanism and key RNA determinants of SARS-CoV-2 Nsp1-induced endonucleolytic cleavage of mRNA

SARS-CoV-2 nonstructural protein 1 (Nsp1) binds to 40S ribosomal subunits and induces host protein synthesis shut off by inhibiting translation initiation and triggering endonucleolytic cleavage of cellular mRNAs. Irrespective of the mode of initiation, Nsp1-mediated cleavage is induced by the cooperative action of the N-terminal domain of Nsp1, the RRM domain of eIF3g and 40S subunits. Using in vitro reconstitution, we determined that cleavage occurs by transesterification following intramolecular nucleophilic attack of the 2OH of the ribose on the adjacent phosphodiester bond yielding 5OH and 2,3 -cyclic phosphate termini. Cleavage requires a guanosine [~]10-22 nucleotides from the 5 end of mRNA, occurs within a narrow window upstream of this G, is most efficient between nucleotides at positions -6/-7 and -7/-8 relative to G, and shows a preference for Pu at positions -7 or -8 which provides the 2OH for the nucleophilic attack. Zero-length UV cross-linking of Nsp1 to nucleotides at positions -1 and -2 suggests that the critical guanosine may be recognized by Nsp1. Resistance to Nsp1-mediated cleavage of SARS-CoV-2 mRNA was ensured both by the relatively long distance between its G23G24 and the 5end and by the preceding oligoPy stretch lacking purines at positions -7 or -8 upstream of G23G24.

Preprint↗