Biology subjects

Martija, A.

Publications and source records attributed to Martija, A..

5 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

Intrinsic coordination of dynamic molecular signatures shape the human prefrontal cortex

The cerebral cortex drives human cognition through the coordinated activity of discrete cortical areas, each harboring specialized molecular, structural and functional characteristics. Central to this organization is the prefrontal cortex (PFC), a hub for executive function that displays disproportionate expansion in humans and selective vulnerability to neurodevelopmental disorders. Previous work has identified a collection of PFC-enriched marker genes with dynamic expression trajectories, and re-analysis of these datasets converge these markers into 18 distinct molecular signatures of spatiotemporal PFC identity. However, the intrinsic gene networks that coordinate these molecular signatures to shape the human PFC remains unclear. Through pooled CRISPR activation screens in human primary cortical tissues, we have evaluated the ability of PFC-enriched transcription factors to intrinsically pattern PFC molecular identity. Our screens identify novel roles for the neurogenesis regulator, YBX1, in the activation of human PFC fate. In parallel screens and knock-down experiments in human cortical organoids, we define how YBX1 acts in concert with other PFC determinants to activate molecular signatures of PFC identity. Our findings support a model in which PFC patterning is orchestrated by cohorts of intrinsic determinants that initiate, potentiate, and modulate PFC gene signatures, conferring robustness to the development of the human PFC.

neuroscience↗

bioRxiv2025

Region-specific human brain organoids reveal synaptic and cell state drivers of glioblastoma invasion

Glioblastoma (GBM) is a highly heterogenous and malignant brain tumor, in part because it disrupts normal brain circuits to fuel its own growth and invasion. Thus, there is a need to identify the molecular features of invasive GBM cells and their regulators in the neural microenvironment. To address this in a fully human model, we engrafted patient-derived GBM cells (total n=15 independent samples) from three sources-- fresh neurosurgical resections, cell lines, and whole GBM organoids--into human induced pluripotent stem cell-derived organoids patterned to forebrain, midbrain, and spinal cord identities. GBM cells from all sources infiltrated brain organoids within 2 days post-engraftment, reaching maximal invasion by day 14. Across organoids of distinct spatial and maturational milieu, GBM cells showed a consistent reduction in astrocyte-like states and an enrichment in neuron/glia progenitor-like (NPC-like) states. These NPC-like GBM cells expressed neuronal and synaptic machinery, and tumors enriched in this transcriptomic state prior to engraftment achieved greater organoid coverage, suggesting enhanced infiltration and synaptic integration of this GBM cell type. Although GBM cell states converged across organoid types after engraftment, infiltration was greater in the forebrain than spinal cord. This is likely reflective of synaptic input from deep-layer TBR1 excitatory neurons in the forebrain, as demonstrated by a combination of rabies-based monosynaptic tracing and single-cell transcriptomics. In contrast, inhibitory neurons were the predominant synaptic partners of GBM in the spinal cord. Together, this fully human model of the neural-GBM connectome reveals how neuron-like GBM states and regionally distinct synaptic inputs cooperatively shape tumor invasion.

neuroscience↗

bioRxiv2025

A Human Tumor-Immune Organoid Model of Glioblastoma

A major obstacle to identifying effective therapies for the aggressive brain tumor glioblastoma is the lack of human-specific, immunocompetent models that reflect the human tumor microenvironment. To address this, we developed the immune-Human Organoid Tumor Transplantation (iHOTT) model. This is an autologous co-culture platform that integrates patient-derived tumor cells and matched peripheral blood mononuclear cells (PBMCs) within human cortical organoids, enabling the study of the patient-specific immune response to the tumor and tumor-immune interactions. This platform preserves tumor and immune populations, immune signaling, and cell-cell interactions observed in patient tumors. Treatment of iHOTT with pembrolizumab, a checkpoint inhibitor, mirrored cell type shifts and cell interactions observed in patients. TCR sequencing further revealed pembrolizumab-driven expansion of stem-like CD4-T-cell clonotypes exhibiting patient-specific repertoires. These findings establish iHOTT as a physiologically relevant platform for exploring autologous tumor-immune interactions and underscore the critical need for antigen-targeted strategies to enhance immunotherapy in glioblastoma.

cancer biology↗

bioRxiv2025

Thalamic NRXN1-Mediated Input to Human Cortical Progenitors Drives Upper Layer Neurogenesis

According to the protocortex hypothesis, extrinsic thalamic signaling is necessary for refining cortical areas and cell types, but the mechanism by which these inputs shape the development and expansion of the human cortex remains largely unexplored. We fuse cortical and thalamic organoids to study this process. Using single-nuclei RNA-sequencing and cellular imaging, we discover that thalamic signals during a critical period promote human cortical upper-layer neurogenesis. In assembloid models and human primary cortex, we find NRXN1 mediates thalamic axon contact with primate-enriched outer radial glia, driving developmental gene expression changes. Genetic perturbation of NRXN1 in thalamic neurons reduces these contacts and attenuates cortical upper-layer neurogenesis. These findings in human developmental models suggest a novel role for thalamic regulation of primate outer radial glia cell fate.

neuroscience↗