Biology subjects

Koptyra, M. P.

Publications and source records attributed to Koptyra, M. P..

4 recordsLinked to original sources

bioRxiv2025

Neuronal cell adhesion molecule (NRCAM) variant defined by microexon skipping is an essential, antigenically distinct, and targetable surface proteoform in high-grade glioma

To overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns in pHGGs and normal brain samples. Among alternative splicing events affecting extracellular protein domains, the most pervasive alteration was the skipping of [≤]30 nucleotide-long exons. Several of these skipped microexons mapped to L1-IgCAM family members, such as NRCAM. Bulk and single-nuclei short- and long-read RNA-seq revealed uniform skipping of NRCAM microexons 5 and 19 in virtually every pHGG sample. Importantly, the {Delta}ex5{Delta}ex19 (but not the full-length) NRCAM proteoform was essential for pHGG cell migration and invasion in vitro and tumor growth in vivo. We developed a monoclonal antibody selective for {Delta}ex5{Delta}ex19 NRCAM and demonstrated that "painting" of pHGG cells with this antibody enables killing by T cells armed with an FcRI-based universal immune receptor. Thus, pHGG-specific NRCAM and possibly other L1-IgCAM proteoforms are promising and highly selective targets for adoptive immunotherapies.

cancer biology↗

bioRxiv2024

A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma

Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it is increasingly recognized as a molecularly distinct, yet highly heterogeneous disease. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients before and after standard therapy through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We found that the canonical neoplastic cell phenotypes of adult glioblastoma are insufficient to capture the range of tumor cell states in a pediatric cohort and observed differential tumor-myeloid interactions between malignant cell states. We identified key transcriptional regulators of pHGG cell states and did not observe the marked proneural to mesenchymal shift characteristic of adult glioblastoma. We showed that essential neuromodulators and the interferon response are upregulated post-therapy along with an increase in non-neoplastic oligodendrocytes. Through in vitro pharmacological perturbation, we demonstrated novel malignant cell-intrinsic targets. This multiomic atlas of longitudinal pHGG captures the key features of therapy response that support distinction from its adult counterpart and suggests therapeutic strategies which are targeted to pediatric gliomas.

cancer biology↗

bioRxiv2022

OpenPBTA: An Open Pediatric Brain Tumor Atlas

SummaryPediatric brain and spinal cancer are the leading disease-related cause of death in children, thus we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Childrens Brain Tumor Network and Pacific Pediatric Neuro-Oncology Consortium created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to create OpenPBTA, an open collaborative project which establishes over 40 scalable analysis modules to genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals that TP53 loss is a significant marker for poor overall survival in ependymomas and H3 K28-altered diffuse midline gliomas and further identifies universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas. OpenPBTA is a foundational analysis platform actively being applied to other pediatric cancers and inform molecular tumor board decision-making, making it an invaluable resource to the pediatric oncology community. In BriefThe OpenPBTA is a global, collaborative open-science initiative which brought together researchers and clinicians to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Shapiro, et. al create over 40 open-source, scalable modules to perform cancer genomics analyses and provide a richly-annotated somatic dataset across 58 brain tumor histologies. The OpenPBTA framework can be used as a model for large-scale data integration to inform basic research, therapeutic target identification, and clinical translation. HighlightsOpenPBTA collaborative analyses establish resource for 1,074 pediatric brain tumors NGS-based WHO-aligned integrated diagnoses generated for 641 of 1,074 tumors RNA-Seq analysis infers medulloblastoma subtypes, TP53 status, and telomerase activity OpenPBTA will accelerate therapeutic translation of genomic insights

genomics↗

bioRxiv2019

Pediatric High Grade Glioma Resources From the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA)

BackgroundPediatric high grade glioma (pHGG) remains a fatal disease. Increased access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Childrens Brain Tumor Tissue Consortium (CBTTC) from the first release (October 2018) of the Pediatric Brain Tumor Atlas (PBTA).\n\nMethodspHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created.\n\nResultsThe pHGG set included 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAF V600E variants). A pHGG TMA (n=77), includes 36 (53%) patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency.\n\nConclusionThe CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.\n\nIMPORTANCE OF STUDYHigh-grade gliomas (HGG) remain the leading cause of cancer death in children. Since molecularly heterogeneous, preclinical studies of pediatric HGG will be most informative if able to compare across groups. Given their relatively rarity, there are few readily available biospecimens and cellular models to inform preclinical laboratory and genomic translational research. Therefore, the aim of this CBTTC study was to highlight the panel of pediatric HGG cases whose primary tumors have undergone extensive genomic analysis, have clinical data, available imaging and additional biospecimens, including tumor, nucleic acids, cell lines and FFPE tissue on a tissue microarray (TMA).

cancer biology↗