Biology subjects

Bessler, N.

Publications and source records attributed to Bessler, N..

3 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↗

bioRxiv2024

BEHAV3D Tumor Profiler to map heterogeneous cancer cell behavior in the tumor microenvironment

Intravital microscopy (IVM) enables live imaging of animals at single-cell level, offering essential insights into cancer progression. This technique allows for the observation of single-cell behaviors within their natural 3D tissue environments, shedding light on how genetic and microenvironmental changes influence the complex dynamics of tumors. IVM generates highly complex datasets that often exceed the analytical capacity of traditional uni-parametric approaches, which can neglect single-cell heterogeneous in vivo behavior and limit insights into microenvironmental influences on cellular behavior. To overcome these limitations, we present BEHAV3D Tumor Profiler (BEHAV3D-TP), a computational framework that enables unbiased single-cell classification based on a range of morphological, environmental and dynamic single cell features. BEHAV3D-TP integrates with widely used 2D and 3D image processing pipelines, enabling researchers without advanced computational expertise to profile cancer and healthy cell dynamics in IVM data. Here, we apply BEHAV3D-TP to study diffuse midline glioma (DMG), a highly aggressive pediatric brain tumor characterized by invasive progression. By extending BEHAV3D-TP to incorporate tumor microenvironment (TME) data from IVM or fixed correlative imaging, we demonstrate that distinct migratory behaviors of DMG cells are associated with specific TME components, including tumor-associated macrophages and vasculature. BEHAV3D-TP enhances the accessibility of computational tools for analyzing the complex behaviors of cancer cells and their interactions with the TME in IVM data.

cancer biology↗