Biology subjects

Perryman, T.

Publications and source records attributed to Perryman, T..

3 recordsLinked to original sources

bioRxiv2026

Glutamatergic neuron-tumor synapses shape human glioblastoma cell states through radial glia plasticity

Glioblastoma (GBM) is a devastating primary brain tumor with remarkable inter- and intra-tumoral heterogeneity. GBM cells assume a spectrum of neurodevelopmental-like phenotypes and co-opt normal neurophysiological processes, which include synaptic integration with their neuronal microenvironment. This is mediated by neuron-tumor synapses (NTS) that predominantly involve glutamatergic receptors, which drive calcium elevations that promote tumor proliferation and invasion. The exact relationship between synaptic signaling and tumor cell fate specification, however, remains largely unexplored. Here, we develop and leverage a synapse-optimized human organoid tumor transplantation (so-HOTT) model of GBM to decipher how glutamatergic signaling impacts GBM lineage trajectories. so-HOTT preserves patient tumor heterogeneity, features excitatory NTS, and enables clonal lineage tracing of tumor cells after NTS perturbations. Genetic and pharmacological inhibition of AMPA and kainate receptors in so-HOTT shifts tumor cell composition from neuronal fates toward progenitor-proximal astrocytic/mesenchymal states. This occurs through the attenuation of calcium signaling and reduced plasticity of malignant radial glia (RG)-like progenitors, a previously unrecognized target of NTS. Through the integration of inputs from the neuronal microenvironment into glutamatergic signaling, progenitor populations modulate their transcriptional programs and cell fate, ultimately shaping GBM tumor heterogeneity. Targeting synaptic input may thus constrain the heterogeneity that fuels GBM adaptation and therapeutic escape.

cancer biology↗

bioRxiv2026

Predictable clonal hierarchies from restricted progenitors provide a framework for cell type-specific therapies in glioblastoma

Extensive molecular profiling has revealed profound heterogeneity in glioblastoma (GBM), yet how cellular lineages organize over time to govern tumor propagation and therapeutic response remains poorly understood. Existing single-cell approaches define transcriptional states but provide limited insight into how clonal dynamics shape functional tumor behavior. Here, we integrate high-complexity combinatorial DNA barcoding with single-cell transcriptomics in direct-from-patient IDH1-wild-type GBM, enabling lineage-resolved mapping of progenitor organization in a human microenvironmental context. Across 235,155 malignant cells from nine tumors, clonal relationships form reproducible lineage tracks in which distinct progenitor populations give rise to specific differentiated cell types, revealing that tumor growth is sustained by multiple non-redundant progenitors rather than a single dominant population. These progenitors exhibit distinct propensities for self-renewal, fate restriction, and cross-compartment interactions, collectively accounting for the full spectrum of tumor states. Using this lineage-resolved framework, we identify complementary drug targets in distinct progenitor compartments and demonstrate that hierarchy-informed combination therapies disrupt progenitor-progenitor interactions and reshape lineage output. These findings move beyond descriptive heterogeneity to define functional logic underlying GBM propagation and establish a generalizable framework for rational, cell type-specific combinatorial therapies.

cancer biology↗

bioRxiv2024

Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity

Glioblastoma (GBM) exhibits developmental programs and marked cellular heterogeneity, yet how these features are organized into connected lineage hierarchies remains unclear. Here we identify a rare tumor-intrinsic population, termed the neurovascular progenitor (NVP), that occupies an intermediate position between the major GBM organizational axes. NVP cells co-express neural progenitor and perivascular transcriptional features, are consistently detected across independent patient cohorts, retain canonical GBM copy-number alterations, and localize in situ in both vessel-associated and parenchymal niches. Using direct-from-patient lineage tracing in a human organoid tumor transplantation system, we show that individual NVP cells clonally generate both neural-like and mesenchymal/vascular-like malignant progeny, providing a concrete lineage link between states that are commonly considered mutually exclusive. Despite comprising [~]1% of tumor cells, NVP-derived lineages account for a majority of observed tumor cell types and disproportionately contribute to cycling compartments. Orthogonally, ablation of NVP-associated programs in an in vivo GBM model remodels tumor composition, elicits compensatory progenitor states, and significantly prolongs survival. Together, these findings position NVP as a fate-restricted yet highly influential lineage intermediate that serves as a functional bridge and organizational nexus within GBM hierarchies, linking population-level lineage architecture to the behavior of a specific progenitor cell type.

cancer biology↗