Single cell spatial analysis identifies regulators of brain tumor initiating cells

Abstract

Glioblastomas (GBMs) are aggressive brain tumors with extensive intratumoral heterogeneity. Here, we used spatial transcriptomics and single-cell ATAC-seq to dissect the transcriptome of distinct anatomical regions of the tumor microenvironment. We identified numerous extracellular matrix (ECM) molecules including biglycan elevated in areas infiltrated with brain tumor-initiating cells (BTICs). Single-cell RNA sequencing showed that the ECM molecules were differentially expressed by cells including injury response versus developmental BTICs. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, and this was associated mechanistically with LDL receptor-related protein 6 (LRP6) binding and activation of the Wnt/β-catenin pathway. Biglycan-overexpressing BTICs grew to a larger tumor mass when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in the GBM microenvironment and suggests biglycan-LRP6 axis as a therapeutic target to curb GBM growth.

Spatially resolved single-cell analysis uncovers protein kinase Cδ-expressing microglia with anti-tumor activity in glioblastoma

“…Cluster 2 was localized to known tumoral regions (Fig. 2F) aligning with the highly proliferative regions observed in H&E-stained slides reported in our previous study (6). Differential expression analysis (DEA) identified differences in GEPs between tumoral spots identified by InferCNV compared to non-tumoral spots within spatial datasets.…”

“…Written informed consent was obtained from all patients prior to the collection of tumor biopsies. The information of patients related to these specimens was described previously (6,39).…”

“…These lines were sequentially cultured, preserved, and authenticated within the University of Calgary BTIC Core. Previously reported identification of two human BTIC lines (BT048 and BT073) was utilized in this study (6,39). Short tandem repeat analysis was conducted for cell line authentication, and routine testing for Mycoplasma contamination was performed using the Venor GeM Mycoplasma Detection Kit (Sigma, MP0025).…”

“…The formidable hurdle in enhancing prognosis for GBM patients lies within the intricate landscape of the tumor microenvironment (TME) within the brain. The brain TME exhibits two pivotal features: it is highly immunosuppressive and profoundly heterogeneous, both of which significantly contribute to the dismal prognosis associated with GBM (4)(5)(6)(7). Unlike other tissues, the brain TME boasts a distinctive composition characterized by a diverse array of functionally specialized organ-resident cells (8).…”

Dermal papilla cell‐secreted biglycan regulates hair follicle phase transit and regeneration by activating Wnt/β‐catenin

“…14,24,44 A study has shown biglycan can affect the expression of β-catenin in the cytoplasm, cell membrane and nucleus of osteosarcoma cells. 45 In 2023, Mirzaei et al 46 reported that elevated levels of biglycan in areas infiltrated with brain tumour-initiating cells (BTICs), and the overexpression of biglycan induced the proliferation rate of BTICs, possibly involved in LRP6 binding and activation of the Wnt/β-catenin pathway. Our above results also suggested the close relation between biglycan and Wnt/β-catenin pathway in hair biology.…”