Biology subjects

Kranendonk, M. E. G.

Publications and source records attributed to Kranendonk, M. E. G..

5 recordsLinked to original sources

bioRxiv2026

Cancer-myeloid cell invasive program in pediatric-type diffuse high-grade glioma

Pediatric-type diffuse high-grade gliomas (pHGGs) are aggressive, heterogeneous brain tumors shaped by intricate cancer-microenvironment cell-cell interactions. Here, we present an integrative multimodal pHGGmap, encompassing over 800,000 cells from 136 patients profiled across transcriptomic, epigenomic, and spatial modalities. Its analysis delineated robust cancer-myeloid cell programs that structured the tumor ecosystem and identified ten distinct cancer cell states, including previously unrecognized developmental and context-responsive programs. Among these, radial glial-like (RG-like) cells exhibited dual stress-adapted and infiltrative phenotypes. Tumor-associated monocyte-derived macrophages and resident microglia engaged in four distinct immunomodulatory programs aligned with specific cancer states. Three conserved multicellular communities were maintained across treatment, including a stable, spatially and transcriptionally linked RG-like/complement-macrophage niche, indicative of cellular co-option and adaptation to support invasion. Longitudinal profiling of a metastatic diffuse midline glioma case showed that RG-like cells predominate during dissemination and remain associated with complement-enriched macrophages, whose reprogramming restores immune activation. pHGGmap establishes a landmark resource for translational discovery. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/701142v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@7ae699org.highwire.dtl.DTLVardef@b95b92org.highwire.dtl.DTLVardef@12adcf9org.highwire.dtl.DTLVardef@1118703_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

De novo H3.3K27M-altered Diffuse Midline Glioma in human brainstem organoids to dissect GD2 CAR T cell function

Diffuse midline glioma (DMG) is a rare yet highly aggressive paediatric cancer primarily arising in the pontine region of the brainstem, necessitating the development of scalable patient-representative models for treatment advance1,2. Here, we developed an FGF4-driven human brainstem organoid model, with high representation of pontine glial lineages. By genetically engineering de novo H3.3K27M-altered DMG, we show that this brainstem glial specification is essential for driving DMG tumorigenesis, resulting in tumours that recapitulate the infiltrative nature and molecular heterogeneity of patient samples. By performing prolonged GD2 CAR T cell treatment in this model, we could mirror variable treatment outcomes as observed in the clinic3,4 and demonstrate a high level of CAR T cell transcriptional heterogeneity. From these CAR T cell functional states, we could identify the most potent effector population and validated NCAM1 as a selection marker for their enrichment. In contrast, NCAM1- cells were linked to a cellular stress response, previously associated to immunotherapy resistance5. Furthermore, incorporating the brain-resident myeloid compartment resulted in DMG-specific, largely immunosuppressive microglia subtypes6. These disease-representative microglia reduced GD2 CAR T cell treatment efficacy and we identified the functional profiles most susceptible to this microglia-dependent immune modulation. Thus, we present a scalable human DMG model with critical applications towards understanding CAR T cell functionality to aid therapy development for this detrimental disease.

cancer biology↗

bioRxiv2025

Single-cell spatial analysis of pediatric high-grade glioma reveals a novel population of SPP1+/GPNMB+ myeloid cells with immunosuppressive and tumor-promoting capabilities

BackgroundPediatric-type diffuse high-grade gliomas (pHGG) are a leading cause of pediatric cancer-related mortality. Although immunotherapy offers a promising treatment avenue, clinical responses in pHGG patients remain limited. A detailed understanding of the tumor immune microenvironment (TIME) is essential for advancing immunotherapeutic strategies. MethodsWe performed single-cell spatial analysis integrating cyclical immunofluorescence imaging and Spatial Molecular Imaging to interrogate the proteomic and transcriptomic landscape of pHGG. A tissue microarray comprising 32 diagnostic patient-derived pHGG samples was utilized to map the spatial distribution of immune and tumor cells. ResultsOur analyses reveal that the pHGG TIME is predominantly composed of myeloid cells, including brain-resident microglia and monocyte-derived macrophages, with only few T cells. A significant subset of these myeloid cells express mesenchymal-like genes and are positive for SPP1 and GPNMB. Spatial mapping further demonstrated that SPP1+/GPNMB+ myeloid cells localize in close proximity to mesenchymal-like tumor cells, and negatively correlate with the location and presence of CD8+ T cells. These cells also express genes related to immunosuppression and epithelial-to-mesenchymal transition, indicating their potential role in establishing an immunosuppressive niche. ConclusionsOur findings reveal a distinct immune landscape in pHGG characterized by SPP1+/GPNMB+ myeloid cells which may contribute to the exclusion of CD8+ T cells. This spatially resolved insight identifies these myeloid cells as promising therapeutic targets and provides a rationale for developing novel immunotherapeutic strategies to improve outcomes in pediatric high-grade gliomas.

cancer biology↗

bioRxiv2021

Distribution of GOPC:ROS1 and other ROS1 fusions in glioma types

The ROS proto-oncogene 1 (ROS1) gene is rearranged in various cancers. The translated fusion protein presents an attractive therapeutic target, since specific inhibitors have been approved for several tumor types. In glioma, ROS1 fusions are frequent within infantile hemispheric glioma, and single case reports on occurrences in other glioma types exist. However, a comprehensive analysis spanning the full width of glioma types and subtypes is lacking. We here assessed the spectrum and distribution of ROS1 fusions by screening >20,000 glioma cases for typical chromosomal alterations, with subsequent RNA-sequencing for confirmation of candidate cases. ROS1 fusions were identified in 16 cases, from low grade pilocytic astrocytoma WHO grade 1 to glioblastoma, IDH wildtype WHO grade 4. Thus, despite being enriched in some tumor types, ROS1 fusions are not pathognomonic for specific glioma types and may consitute a relevant target in a variety of cases.

genomics↗

bioRxiv2021

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial ependymoma

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of largely ependymoma-like tumors. Immunohistochemically, tumors were GFAP-positive and OLIG2- and SOX10-negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. Consistent with other fusion-positive ependymal groups, all tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Analysis of time to progression or recurrence revealed survival times comparable to those of patients with ZFTA:RELA-fused ependymoma. In summary, our findings suggest the existence of a novel group of supratentorial ependymomas that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

cancer biology↗