Biology subjects

Uhrbom, L.

Publications and source records attributed to Uhrbom, L..

5 recordsLinked to original sources

bioRxiv2026

Identification of an epigenetically and phenotypically distinct peritumoral glioblastoma cell population linked to inferior patient outcome

Glioblastoma (GB) is an aggressive and therapy-resistant primary brain tumor with dismal prognosis. Lethality is in most patients caused by a local peritumoral (Edge) relapse near the resection cavity. This region is insufficiently studied and experimental models are scarce. We have analyzed matched tissue samples and cell cultures from bulk tumors and Edge regions of 11 GB patients. Genomic profiling displayed similar genetic alterations and subclonal distributions of matched bulk and Edge regions. Functional, phenotypic and combined single nucleus (sn) RNA-seq and ATAC-seq analyses showed distinct differences between bulk and Edge GB cells with similar shifts across patients. Sn multiomics uncovered a subset of Edge cells defined by unique chromatin accessibility signatures and elevated mesenchymal and immune gene expression. Integrated computational and functional investigations converged on microglia-derived Oncostatin-M as a driver of the Edge-unique phenotype, and high expression of Edge-related signatures correlated with inferior patient outcome in independent GB cohorts.

cancer biology↗

bioRxiv2024

Cellular and molecular events organizing the assembly of tertiary lymphoid structures in glioblastoma

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates associated with improved prognosis in numerous tumors. To date, their prognostic value in central nervous system cancers and the events underlying their formation remain unclear. Here, we find that TLS correlate with improved survival in glioblastoma patients. Furthermore, combining spatial transcriptomics of human tissues with longitudinal studies in murine glioma, we establish that the assembly of T cell-rich clusters is a prerequisite for the development of canonical TLS, and show that CD4 T cells play a central role in this process. Indeed, we provide evidence that IL7R+CCR7+ Th1 lymphocytes with lymphoid tissue-inducing potential are recruited to TLS nucleation sites, where they can initiate TLS assembly by expressing lymphotoxin {beta}. Our work defines TLS as a potential prognostic factor in glioblastoma and identifies cellular and molecular mechanisms of TLS formation. These findings have broader implications for the development of TLS-inducing therapies for cancer. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/601824v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@78be05org.highwire.dtl.DTLVardef@1037706org.highwire.dtl.DTLVardef@7b64e1org.highwire.dtl.DTLVardef@11bfd5c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Glioblastoma stem cells express non-canonical proteins and exclusive mesenchymal-like or non-mesenchymal-like protein signatures

Glioblastomas (GBM) origin, recurrence and resistance to treatment are driven by GBM cancer stem cells (GSCs). Existing transcriptomic characterisations of GBM classify the tumours to three subtypes: classical, proneural, and mesenchymal. The comprehension of how expression patterns of the GBM subtypes are reflected at global proteome level in GSCs is limited. To characterise protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry proteomics. We identified and quantified over 10,000 proteins in two independent GSCs panels, and propose a GSC-associated proteomic signature (GSAPS) that defines two distinct morphological conditions; one defined by a set of proteins expressed in non-mesenchymal - proneural and classical - GSCs (GPC-like), and another expressed in mesenchymal GSCs (GM-like). The expression of GM-like protein set in GBM tissue was associated with hypoxia, necrosis, recurrence, and worse overall survival in GBM patients. In a proof-of-concept proteogenomic approach, we discovered 252 non-canonical peptides expressed in GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered protein-non-coding. We report new variants of the heterogeneous ribonucleoproteins (HNRNPs), which are implicated in mRNA splicing. Furthermore, we show that per-gene mRNA-protein correlations in GSCs are moderate and vary compared to GBM tissue.

cancer biology↗

bioRxiv2021

Conserved cell-lineage controlled epigenetic regulation in human and mouse glioblastoma stem cells determines functionally distinct subgroups

There is ample support for developmental regulation of glioblastoma stem cells (GSCs). To examine how cell lineage controls GSC function we have performed a cross-species epigenome analysis of mouse and human GSC cultures. We have analyzed and compared the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered a variability of both mouse and human GSC cultures that was different from transcriptome analysis and better at predicting functional subgroups. In both species the chromatin accessibility-guided clusters were predominantly determined by distal regulatory element (DRE) regions, displayed contrasting sets of transcription factor binding motifs, and exhibited different functional and drug-response properties. Cross-species analysis of DRE regions in accessible chromatin revealed conserved epigenetic regulation of mouse and human GSCs. Human ATAC-seq data produced three distinct clusters with significant overlap to our previous mouse cell of origin- based stratification, where two of the clusters displayed significantly different patient survival. We conclude that epigenetic regulation of GSCs primarily is dictated by developmental origin which controls key GSC properties and affects therapeutic response.

neuroscience↗

bioRxiv2019

Live detection of neural stem and glioblastoma cells by an oligothiophene derivative

Here we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) cells and embryonic neural stem cells (NSCs). While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. p-HTMI were readily able to detect a subpopulation of human cells in vivo in mouse brain sections with tumors developed from orthotopically transplanted patient-derived GBM cells. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of subpopulations of neural stem and glioma cells.

bioengineering↗