Biology subjects

Nakamura, B.

Publications and source records attributed to Nakamura, B..

4 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↗

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↗

bioRxiv2019

Population specific reference panels are crucial for the genetic analyses of Native Hawai’ians: an example of the CREBRF locus

Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals,, further contributing to the obstacles to study these populations. Here we examined the consequences due to the lack of representation by genotyping a functionally important, Polynesian-specific variant, rs373863828, in the CREBRF gene, in a large number of self-reported Native Hawaiians (N=3,693) from the Multiethnic Cohort. We found the derived allele of rs373863828 was significantly associated with several adiposity traits with large effects (e.g. 0.214 s.d., or approximately 1.28 kg/m2, per allele, in BMI as the most significant; P = 7.5x10-5). Due to the current absence of Polynesian representation in publicly accessible reference sequences, rs373863828 or any of its proxies could not be tested through imputation using these existing resources. Moreover, the association signals at this Polynesian-specific variant could not be captured by alternative approaches, such as admixture mapping. In contrast, highly accurate imputation can be achieved even if a small number (<200) of Polynesian reference individuals were available. By constructing an internal set of Polynesian reference individuals, we were able to increase sample size for analysis up to 3,936 individuals, and improved the statistical evidence of association (e.g. p = 1.5x10-7, 3x10-6, and 1.4x10-4 for BMI, hip circumference, and T2D, respectively). Taken together, our results suggest the alarming possibility that lack of representation in reference panels would inhibit discovery of functionally important, population-specific loci such as CREBRF. Yet, they could be easily detected and prioritized with improved representation of diverse populations in sequencing studies.

genetics↗