A5071625660- FOXO transcription factor regulation
- Protein Degradation and Inhibitors
- Cancer Immunotherapy and Biomarkers
- Chromatin Remodeling and Cancer
- CAR-T cell therapy research
- Sarcoma Diagnosis and Treatment
- Cancer-related molecular mechanisms research
- Radiomics and Machine Learning in Medical Imaging
- Immunotherapy and Immune Responses
- Marine Ecology and Invasive Species
- RNA modifications and cancer
- Pluripotent Stem Cells Research
- Animal Genetics and Reproduction
- Marine Biology and Environmental Chemistry
- Echinoderm biology and ecology
- Neuroblastoma Research and Treatments
- Insect Resistance and Genetics
- Cancer Genomics and Diagnostics
- Virus-based gene therapy research
- Genomics and Chromatin Dynamics
- Gene expression and cancer classification
- Genomics and Phylogenetic Studies
- Tumors and Oncological Cases
- Infant Nutrition and Health
- Research on Leishmaniasis Studies
National Cancer Institute
2016-2025
National Institutes of Health
2017-2024
Center for Cancer Research
2015-2024
St. Jude Children's Research Hospital
2018-2020
ORCID
2020
Iowa State University
2012-2018
University of Chicago
2014
Abstract Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3–FOXO1. The mechanisms which PAX3–FOXO1 dysregulates chromatin are unknown. We find reprograms cis-regulatory landscape inducing de novo super enhancers. uses enhancers to set up autoregulatory loops in collaboration with master factors MYOG, MYOD, MYCN. This enhancer circuitry consistent across cell lines primary tumors....
PURPOSE Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available risk stratification. We present an international consortium study designed to determine incidence driver mutations their association clinical outcome. PATIENTS AND METHODS Tumor samples collected from enrolled on Children's Oncology...
With investigators looking to expand engineered T cell therapies such as CAR-T new tumor targets and patient populations, a variety of manufacturing platforms have been developed scale capacity using closed and/or automated systems. Such are particularly useful for solid targets, which typically require higher doses. Although phenotype function key attributes that often correlate with therapeutic efficacy, how influence the final product is currently unknown. We compared 4 commonly used...
MEK inhibition decreases cell viability and induces differentiation in RAS-driven rhabdomyosarcoma via an epigenetic mechanism.
Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated (TAAs), limited persistence, and exhaustion. Here, we aimed identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed neuroblastoma (NB), a lethal extracranial tumor childhood. First, examined CAR expansion the presence targets by digital droplet PCR....
We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes 131 cell lines 147 normal tissue for comparison. describe patterns infiltrating immune cells, T receptor (TCR) clonal expansion, translationally relevant checkpoints. find that tumor-infiltrating lymphocytes TCR counts vary widely across types within each diagnosis, notably are significantly...
Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting are lacking. Here, we screen 62,643 compounds using engineered cell line that monitors transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm inhibition of multiple KDMs with highest...
Abstract Temporal regulation of super-enhancer (SE) driven transcription factors (TFs) underlies normal developmental programs. Neuroblastoma (NB) arises from an inability sympathoadrenal progenitors to exit a self-renewal program and terminally differentiate. To identify SEs driving TF regulators, we use all-trans retinoic acid (ATRA) induce NB growth arrest differentiation. Time-course H3K27ac ChIP-seq RNA-seq reveal ATRA coordinated SE waves. that decrease with link stem cell development...
Rhabdomyosarcoma (RMS) is an aggressive pediatric malignancy of the muscle, that includes Fusion Positive (FP)-RMS harboring PAX3/7-FOXO1 and Negative (FN)-RMS commonly with RAS pathway mutations. RMS express myogenic master transcription factors MYOD MYOG yet are unable to terminally differentiate. Here, we report SNAI2 highly expressed in FN-RMS, oncogenic, blocks differentiation, promotes growth. activates via super enhancers striped 3D contact architecture. Genome wide chromatin binding...
Abstract Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype characterized by t(2;13) or t(1;13) translocations encoding for PAX3- PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). gene alters the myogenic program maintains proliferative state while blocking terminal differentiation. Here, we investigated contributions chromatin regulatory complexes FP-RMS tumor maintenance....
Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor 4 (FGFR4) highly expressed in RMS lowly healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as adoptive T cell treatment for RMS. 3A11 CAR cells induced robust cytokine production...
CD19 chimeric antigen receptor T-cell therapy (CD19-CAR) has changed the treatment landscape and outcomes for patients with pre-B-cell acute lymphoblastic leukemia (B-ALL). Unfortunately, primary nonresponse (PNR), sustained CD19+ disease, concurrent expansion of CD19-CAR occur in 20% is associated adverse outcomes. Although some failures may be attributable to loss, mechanisms CD19-independent, leukemia-intrinsic resistance remain poorly understood. We hypothesize that PNR leukemias are...
Motility and the coordination of moving food through gastrointestinal tract rely on a complex network neurons known as enteric nervous system (ENS). Despite its critical function, many molecular mechanisms that direct development ENS elaboration neural connections remain unknown. The goal this study was to transcriptionally identify pathways candidate genes drive specification, differentiation circuitry specific progenitors, phox2b expressing cell lineage, during normal development. Because...
Abstract BACKGROUND: Oncogenic fusion genes are attractive therapeutic targets due to their tumor-specific expression and driver roles in cancer. PAX3::FOXO1 (P3F) is the dominant oncogenic of fusion-positive rhabdomyosarcoma (FP-RMS) with no current targeted therapy. METHOD: HiBiT tag, an 11 amino acid peptide NanoLuc luciferase, was inserted into C-terminal end endogenous P3F using CRISPR. Western used for tag validation. RNA-seq ChIP-seq were assess transcriptomics DNA binding...
The highly conserved <I>wnt</I> gene family has roles in developmental processes ranging from axis formation to cell fate determination. polychaete <I>Platynereis dumerilii</I> retained 12 of the 13 ancient subfamilies and is a good model system study ligands spiralian development. While it been shown that <I>Platynereis</I> uses global beta-catenin-mediated binary specification module development, early genes present are unknown. Transcriptional profiling by RNA-Seq during development...
A consistent correlation between tumor mutation burden (TMB) and immune microenvironment has not been observed in gliomas as other cancers.Driver germline somatic mutations, TMB, neoantigen, cell signatures were analyzed using whole exome sequencing (WES) transcriptome of WES matched DNA a cohort 66 glioma samples (44 IDH-mutant 22 IDH-wildtype).Fourteen revealed hypermutator phenotype (HMP). Eight pathogenic (P) or likely (LP) variants detected 9 (19%) patients. Six these 8 genes damage...
Abstract Purpose: Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit vitro and vivo efficacy against preclinical models rhabdoid tumor. Experimental Design: screened eight tumor cell lines with 481 compared their sensitivity 879 other cancer lines. Genome-scale CRISPR–Cas9 inactivation screens were analyzed confirm target vulnerabilities. Gene expression data queried across primary discover biomarkers...
Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations RMS, strongly correlated with survival; however, predicting these mutations or high-risk disease at diagnosis remains a significant challenge. In this study, we utilized convolutional neural networks (CNN) to learn histologic features associated driver outcome using hematoxylin eosin (H&E) images of RMS.Digital whole slide H&E...
The spiral cleavage mode of early development is utilized in over one-third all animal phyla and generates embryonic cells different size, position, fate through a conserved set stereotypic invariant asymmetric cell divisions. Despite the widespread use cleavage, regulatory molecular features for any spiral-cleaving embryo are largely uncharted. To address this gap we RNA-sequencing on spiralian model Platynereis dumerilii to capture quantify first complete genome-wide transcriptional...
Wnt signaling pathways are highly conserved signal transduction important for axis formation, cell fate specification, and organogenesis throughout metazoan development. Within the various pathways, frizzled transmembrane receptors (Fzs) secreted frizzled-related proteins (sFRPs) play central roles in receiving antagonizing signals, respectively. Despite their importance, very little is known about gene family (fzs & sfrps) lophotrochozoans, especially during early stages of spiralian Here...
The marine polychaete annelid Platynereis dumerilii has recently emerged as a prominent organism for the study of development, evolution, stem cells, regeneration, ecology, chronobiology and neurobiology within metazoans. Its phylogenetic position spiralian/ lophotrochozoan clade, comparatively high conservation ancestral features in genome, experimental access to any stage its life cycle, make an important model elucidating complex regulatory functional molecular mechanisms governing early...
Abstract Chimeric antigen receptor (CAR) T-cells targeting Fibroblast Growth Factor Receptor 4 (FGFR4), a highly expressed surface tyrosine in rhabdomyosarcoma (RMS), are already the clinical phase of development, but tumour heterogeneity and suboptimal activation might hamper their potency. Here we report an optimization strategy co-stimulatory properties FGFR4 CAR. We replace CD8 hinge transmembrane domain 4-1BB with those CD28. The resulting CARs display enhanced anti-tumor activity...
Abstract Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here and transcriptomic landscapes of solid from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated at diagnosis, one-third classified as having a pediatric high TMB. Prior chemotherapy exposure influenced landscape these tumors, more...