Biology subjects

Neman, J.

Publications and source records attributed to Neman, J..

5 recordsLinked to original sources

bioRxiv2026

A Microneurosurgical Survival Platform for Elucidating Mechanisms of Brain Tumor Recurrence and Metastasis

Brain tumor recurrence remains the leading cause of mortality in neuro-oncology, and there is a lack of preclinical models replicating the clinical cycle of surgical resection and relapse. To bridge this gap, we developed a novel microneurosurgical survival platform in mice using the NICO Myriad system. We orthotopically implanted pediatric medulloblastoma cells into the mouse cerebral cortex or cerebellum, followed by longitudinal microneurosurgical resection. Bioluminescence imaging and gross fluorescence verified successful resection, local and distal recurrence and metastasis. Comparative bulk RNA sequencing revealed extensive stage-specific transcriptomic divergence alongside conserved core gene sets (2,702 genes in the cerebral cortex and 3,240 genes in the cerebellum) across primary, locally recurrent, and distally recurrent stages. Pathway analysis shows activation of cellular growth, second messenger signaling, and cellular stress adaptation pathways. Targeted qPCR validation demonstrated that post-surgical relapse is driven by a distinct molecular program: recurrent tumors downregulate primary developmental drivers (PTCH1, MYCBP2), canonical suppressors (FOS, PTEN), and chromatin regulators (HDAC2), while selectively upregulating post-transcriptional machinery (RBM8A), endosomal trafficking regulators (RAB5C), acetyltransferases (NAA15), and the m6A RNA demethylase ALKBH5. These findings reveal that medulloblastoma shifts from a primary oncogenic state toward post-transcriptional and transcriptomic survival mechanisms following surgery. Identifying persistent candidates within this conserved core framework provides a roadmap for next-generation precision immunotherapies.

cancer biology↗

bioRxiv2026

Chromosome 2q31.2 Deletion Impairs Neuronal Plasticity through Integrated Stress Response Activation

Rare genomic deletions disrupt gene networks essential for neural development and synaptic plasticity, yet their mechanistic effects remain poorly understood. Here, we investigated the impact of a chromosome 2q31.2 deletion using induced pluripotent stem cell (iPSC)-derived neural models from an affected individual and a genetically matched parental control. Differentiation into neural precursor cells and glial lineages was maintained, with subtle changes in cytoskeletal and lineage-associated gene expression. Transcriptomic analysis showed activation of oxidative stress, mitochondrial dysfunction, and degeneration-linked pathways, consistent with engagement of the integrated stress response (ISR). Pharmacologic inhibition of the ISR with ISRIB reduced ATF4 expression in neural precursors and mature neurons and increased CREB phosphorylation throughout development. Functionally, ISRIB improved neuronal network activity in cortical organoids, increasing calcium burst amplitude and synchronization after NMDA and AMPA stimulation. These results identify ISR dysregulation as a mechanistic link between chromosome 2q31.2 deletion and impaired neuronal plasticity, highlighting ISR modulation via ISRIB as a potential therapeutic approach.

neuroscience↗

bioRxiv2026

A class act: HDAC1-Malat1 regulates MDSC apoptosis and cell cycling to decrease suppression of T cells

Myeloid derived suppressor cells (MDSCs) are key players in the immune-suppressed tumor microenvironment (TME) and significantly contribute to immune checkpoint inhibition (ICI) resistance, making them favorable targets for cancer immunotherapy. Epigenetic reprogramming of MDSCs using histone deacetylase (HDAC) inhibitors shows promise to sensitize the TME to ICIs. However, the molecular mechanism of HDAC inhibition in MDSCs has yet to be elucidated. Murine and human MDSC models treated with Entinostat revealed that the long non-coding RNA Malat1 downregulates pSTAT3 and decreases MDSC-mediated suppression of T cell proliferation. Through HDAC inhibitor screens, we identified HDAC1 as preferentially regulating Malat1 expression, STAT3 activation, and MDSC suppression. We also show that HDAC1 inhibition increases MDSC apoptosis by shifting pro-vs. anti-apoptotic signals and increases G0/G1 cell cycle arrest via decreasing G1-S transition cyclin-CDK complexes. Collectively, our findings provide a multi-pronged mechanism of HDAC inhibition in MDSCs that inform the development of future rational combination therapies. One Sentence SummaryHDAC1 inhibition in MDSCs increases Malat1, decreases pSTAT3, induces apoptosis/cell cycle arrest, and decreases suppression of T cells

immunology↗

bioRxiv2025

AI-Driven and 3D-Bioprinted New Approach Methodology (NAM) Identifies NEO100 as Potent Ultrasound-Activated Therapeutic for Primary and Metastatic Brain Tumors

Primary and metastatic brain tumors are among the deadliest and treatment-resistant cancers, mainly because of their inherent resistance to chemoradiation and limited drug delivery across the blood-brain barrier (BBB). Identifying molecules that can cross the BBB and serve as sonosensitizers is crucial for developing noninvasive, targeted therapies such as sonodynamic therapy (SDT). To overcome the limitations of traditional low-throughput screening, a New Approach Methodology (NAM) was developed, starting with AI-driven molecular discovery. A positive-unlabeled neural network, trained on over 200 molecular descriptors, was used to predict compounds likely to respond to focused ultrasound (FUS), penetrate the BBB, and mediate therapeutic sonodynamic activity. While AI helps prioritize potent candidates, effective SDT also depends on clinically scalable FUS delivery. Low-intensity FUS enables noninvasive activation of small molecules in the brain and has been validated in several clinical settings. Therefore, AI-guided predictions were combined with ultrasound-based sonodynamic testing using parameters relevant to human therapy. A major challenge in SDT development is the lack of rapid, physiologically relevant tumor models, as traditional 3D organoids take weeks to mature, delaying validation. To address this, a magnetic bioprinting platform was used to produce uniform 3D tumor spheroids within hours, enabling high-throughput screening of SDT. These spheroids replicate key microenvironmental gradients, supporting reliable ultrasound-driven cytotoxicity testing. Through this combined NAM pipeline, AI identified NEO100--an ultrapure, pharmaceutical-grade perillyl alcohol currently in Phase 2a clinical trials--as a promising sonosensitizer candidate. These predictions were validated in rapidly 3D bioprinted tumor models representing glioblastoma, Group 3 pediatric medulloblastoma, meningioma, and breast-to-brain and lung-to-brain metastases. In all tumor types, ultrasound activation significantly increased NEO100s cytotoxicity. Given its established safety profile in humans and ability to cross the BBB, NEO100 demonstrates how integrating AI-based molecular discovery, accelerated 3D bioprinting, and clinically relevant ultrasound parameters can rapidly advance precision sonodynamic therapies for various primary and metastatic brain cancers.

cancer biology↗

bioRxiv2024

Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis

Myeloid Derived Suppressor Cells (MDSCs) support breast cancer growth via immune suppression and non-immunological mechanisms. Although 15% of patients with breast cancer will develop brain metastasis, there is scant understanding of MDSCs contribution within the breast-to-brain metastatic microenvironment. Utilizing co-culture models mimicking a tumor-neuron-immune microenvironment and patient tissue arrays, we identified serotonergic receptor, HTR2B, on MDSCs to upregulate pNF-{kappa}B and suppress T cell proliferation, resulting in enhanced tumor growth. In vivo murine models of metastatic and intracranial breast tumors treated with FDA-approved, anti-psychotic HTR2B antagonist, clozapine, combined with immunotherapy anti-PD-1 demonstrated a significant increase in survival and increased T cell infiltration. Collectively, these findings reveal a previously unknown role of MDSC-HTR2B in breast-to-brain metastasis, suggesting a novel and immediate therapeutic approach using neurological drugs to treat patients with metastatic breast cancer.

cancer biology↗