Abstract BACKGROUND Pediatric brain and spinal cord tumors are the leading cause of cancer-related mortality in children. An incomplete understanding of brain tumor biology and associated limited ...access to high-quality biological samples for research are the main factors driving the lack of clinical therapeutic development for pediatric brain tumors that recur or progress. Post-mortem tissue donation provides an unprecedented resource for addressing some of these limitations. METHODS The Gift from a Child (GFAC) program by the Swifty Foundation has a unique mission to increase post-mortem pediatric brain tissue donations through advocacy as well as the education of clinicians and families. Through GFAC’s strategic collaboration with the Children’s Brain Tumor Network (CBTN), CBTN has leveraged postmortem tissue to expand the Pediatric Brain Tumor Atlas (PBTA), a cross-histology multi-omics atlas resource. As part of the effort CBTN has sequenced and released data for over 350 post-mortem pediatric brain tumor specimens including multiple brain region sampling cases with specimen and sequencing quality metrics. RESULTS Here we present an assessment of postmortem samples and available multi-omic data on postmortem samples within the PBTA dataset. Data have been harmonized and released with no publication embargo. To access data, researchers can utilize existing open source data resources and platforms including PedCbioPortal and OpenPedCan to: (1) Identify tumor spatial and temporal specific alterations (2) Establish tumor evolution trajectory leading to therapeutic resistance and tumor progression; (3) Understand tumor heterogeneity longitudinally across multiple ‘omics layers; and (4) Identify and request specimens and derived tumor models. CONCLUSIONS Together, we present the largest deeply characterized cohort of postmortem pediatric brain tumor samples as powerful expansion of the PBTA cohort of >3,000 pediatric brain tumors. CBTN’s open-science model supported by the GFAC mission highlights the value and utility of autopsy-based specimen collection on behalf of improving outcomes for children with brain tumors.
Abstract
Pediatric brain tumor preclinical development has suffered from the lack of robust in vitro and in vivo models that span the large number of brain tumor histologies. Opportunities for ...precision medicine approaches for solid and brain tumors are expanding, including immunotherapies, so it is essential to maximize access to preclinical models for studies of specificity, efficacy, and safety of treatments in ways that align patient models to patient samples and their clinical course. The Children’s Brain Tumor Network (CBTN) seeks to accelerate pediatric brain tumor research and discovery through support of the tumor model development program paired with molecularly characterized patient samples and longitudinal clinical data. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide. Here we present currently available preclinical model resources comprising over 150 cell lines, organoids, and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the use of tumor tissue to generate a combination of cell lines, organoids and/or xenograft models grown in animals. To date, consortium-supported lines have been provided internationally to over 50 projects, encompassing basic biology and translational studies. Molecular data (whole genome sequencing and RNAseq) is currently available for over 80 models and a substantial portion of that cohort undergoes additional large-scale data generation and drug testing through collaborative work with Childhood Cancer Model Atlas, ProCan, and National Center for Advancing Translational Sciences. All models’ data are accompanied with patient molecular and clinical longitudinal information accessible through Kids First Data Resource, CAVATICA and PedcBio portals. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission – to accelerate therapeutic discovery for children suffering from brain tumors.
Self‐assembling protein nanoparticles are a promising class of materials for targeted drug delivery. Here, the use of a computationally designed, two‐component, icosahedral protein nanoparticle is ...reported to encapsulate multiple macromolecular cargoes via simple and controlled self‐assembly in vitro. Single‐stranded RNA molecules between 200 and 2500 nucleotides in length are encapsulated and protected from enzymatic degradation for up to a month with length‐dependent decay rates. Immunogenicity studies of nanoparticles packaging synthetic polymers carrying a small‐molecule TLR7/8 agonist show that co‐delivery of antigen and adjuvant results in a more than 20‐fold increase in humoral immune responses while minimizing systemic cytokine secretion associated with free adjuvant. Coupled with the precise control over nanoparticle structure offered by computational design, robust and versatile encapsulation via in vitro assembly opens the door to a new generation of cargo‐loaded protein nanoparticles that can combine the therapeutic effects of multiple drug classes.
The use of a computationally designed, two‐component icosahedral protein nanoparticle is reported to encapsulate multiple macromolecular cargoes via simple and controlled self‐assembly in vitro. In addition, immunogenicity studies of nanoparticles packaging synthetic polymers carrying a small‐molecule TLR7/8 agonist increase humoral immune responses while minimizing systemic cytokine release.
Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of ...sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to stimulation: male microglia tended to have a more pro-inflammatory phenotype, while female microglia showed increased sensitivity to conduritol-B-epoxide (CBE), a small molecule inhibitor of glucocerebrosidase, the enzyme encoded by the GBA1 gene, mutations of which are the major risk factor for Parkinson's Disease (PD). Interestingly, glucocerebrosidase inhibition particularly impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons, attenuating the sex differences observed in this neuroprotective function. This finding is consistent with the clinical impact of GBA1 mutations, in which the 1.5-2-fold reduced risk of developing idiopathic PD observed in female individuals is lost in the GBA1 carrier population, thus suggesting a sex-specific role for microglia in the etiopathogenesis of PD-GBA1.
