Biology subjects

Chapman, O. S.

Publications and source records attributed to Chapman, O. S..

6 recordsLinked to original sources

bioRxiv2025

Preservation and Clonal Behavior of Extrachromosomal DNA in Patient-Derived Xenograft Models of Childhood Cancers

Extrachromosomal DNA (ecDNA) is a powerful oncogenic driver linked to poor prognosis in pediatric cancers. Whole-genome sequencing of 338 patient-derived xenograft (PDX) samples and 127 matched primary tumors across multiple childhood cancer types was used to compare ecDNA prevalence, sequence conservation, and clonal dynamics. ecDNA in PDX models frequently mirrored oncogene amplifications observed in patient tumors (e.g., MYCN, MYC, MDM2) and showed high sequence conservation. Medulloblastoma and neuroblastoma PDXs exhibited significantly higher ecDNA prevalence, consistent with strong selection or de novo formation during tumor propagation. Although ecDNA copy numbers were generally preserved, some neuroblastoma PDXs displayed marked MYCN copy gains. Single-cell multiome profiling revealed that ecDNA-positive clones either persisted or expanded dramatically in PDXs, in one case growing from a minor subpopulation to nearly all tumor cells. These findings establish PDX models as valuable systems for ecDNA research and underscore the selective growth advantage conferred by ecDNA during tumor evolution.

genomics↗

bioRxiv2025

Ras-Responsive Element Binding Protein 1 regulates survival of Group 3 medulloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and Group 3 (G3, MYC-driven) MB has the worst prognosis. Despite advances in molecular classification, oncogenic drivers of G3 MB remain poorly defined. To identify such drivers, we profiled transcription factor expression across MB subgroups. Our analysis revealed Ras-responsive element binding protein 1 (RREB1) as one of the most highly expressed transcription factors in G3 MB. RREB1 knockdown impaired cell proliferation in vitro and prolonged survival in orthotopic xenograft models, suggesting it plays a key role in regulating tumor growth. Mechanistically, RREB1 acts by enhancing transcription of TGF-{beta} pathway genes. Upstream, RREB1 expression is controlled by c-MET signaling, and the MET inhibitor SU11274 decreased RREB1 levels and MB cell viability. Local delivery of SU11274 in tumor-bearing mice suppressed RREB1 expression and extended survival. These results establish the c-MET/RREB1 axis as a critical oncogenic regulator and a promising therapeutic target in in high-risk MB.

cancer biology↗

bioRxiv2025

Synergistic RAS-MAPK and AKT Activation in MYC-Driven Tumors via Adjacent PVT1 Rearrangements

MYC-driven (MYC+) cancers are aggressive and often fatal. MYC dysregulation is a key event in these cancers, but overexpression of MYC alone is not always enough to cause cancer. Plasmocytoma Variant Translocation 1 (PVT1), a long non-coding RNA (lncRNA) adjacent to MYC on chromosome 8 is a rearrangement hotspot in many MYC+ cancers. In addition to being co-amplified with MYC, the genomic rearrangement at PVT1 involves translocation, which has had obscure functional consequences. We report that translocation at the PVT1 locus cause asymmetric enrichment of 5-PVT1 and loss of 3-PVT1. Despite being classified as a non-coding RNA, the retained 5 region of PVT1 generates a circular RNA (CircPVT1) that codes for the novel peptide we call Firefox (FFX). FFX augments AKT signaling and synergistically activates MYC and mTORC1 in these cells. Further, the 3 end of PVT1, which is lost during the translocation, codes for a tumor-suppressing micropeptide we named as Honeybadger (HNB). We demonstrate that HNB interacts with KRAS and disrupts the activation of KRAS effectors. Loss of HNB leads to activation of RAS/MAPK signaling pathway, and enhances MYC stability by promoting phosphorylation of MYC at Ser62. These findings identify PVT1 as a critical node that synchronizes MYC, AKT, and RAS-MAPK activities in cancer. Our study thus identifies a key mechanism by which rearrangements at the PVT1 locus activate additional oncogenic pathways that synergize with MYC to exacerbate the aggressiveness of MYC+ cancers. This newfound understanding explains the poor prognosis associated with MYC+ cancers and offers potential therapeutic targets that could be leveraged in treatment strategies for these cancers.

cancer biology↗

bioRxiv2025

Reconstructing the three-dimensional architecture of extrachromosomal DNA with ec3D

Extrachromosomal DNAs (ecDNAs) are large, acentric, circular DNA molecules that occur pervasively across many human cancers. EcDNA can drive tumor formation and evolution, contribute to drug resistance, and associate with poor patient survival outcomes. Beyond mediating high copy numbers, the circular topology and dynamic conformational changes of ecDNA disrupt topological domains and rewire regulatory networks, thereby conferring an important role in the transcriptional regulation of oncogenes. Here, we develop ec3D, a computational method for reconstructing the three-dimensional structures of ecDNA and analyzing significant interactions from high-throughput chromatin capture (Hi-C) data. Given a candidate ecDNA sequence and the corresponding whole-genome Hi-C as input, ec3D reconstructs the spatial structure of ecDNA by maximizing the Poisson likelihood of observed interactions. Ec3Ds performance was validated using both simulated ecDNA structures with varying conformations and Hi-C data from previously-characterized cancer cell lines. Our reconstructions reveal that ecDNAs occupy spherical configurations and mediate unique long-range interactions involved in gene regulation. Through algorithmic innovations, ec3D can resolve complex ecDNA structures with duplicated genomic segments, identify multi-way interactions, and distinguish between interactions arising from direct spatial proximity and secondary interactions resulting from alternative folding patterns or intermolecular (trans) contacts of ecDNA molecules. Our findings provide insights into how the spatial organization of ecDNA may influence gene regulation and contribute to increased oncogene expression. Code availabilityhttps://github.com/AmpliconSuite/ec3D

cancer biology↗

bioRxiv2024

ecPath detects ecDNA in tumors from histopathology images

Circular extrachromosomal DNA (ecDNA) can drive tumor initiation, progression and resistance in some of the most aggressive cancers and is emerging as a promising anti-cancer target. However, detection currently requires costly whole-genome sequencing (WGS) or labor-intensive cytogenetic or FISH imaging, limiting its application in routine clinical diagnosis. To overcome this, we developed ecPath (ecDNA from histopathology), a computational method for predicting ecDNA status from routinely available hematoxylin and eosin (H&E) images. ecPath implements a deep-learning method we call transcriptomics-guided learning, which utilizes both transcriptomics and H&E images during the training phase to enable successful ecDNA prediction from H&E images alone, a task not achievable with models trained on H&E images only. It is trained on more than 6,000 tumor whole-slide images from the TCGA cohort with the best performance in predicting ecDNA status in brain and stomach tumors (average AUC=0.78). ecPath revealed that ecDNA-positive tumors are enriched with pleomorphic, larger and high-density nuclei. Testing in an independent cohort, ecPath predicted ecDNA status of 985 pediatric brain tumor patients with an AUC of 0.72. Finally, we applied ecPath to identify ecDNA-positive tumors in the TCGA cohort for which no WGS data were available. Like WGS-based ecDNA-positive labels, the predicted ecDNA-positive status also identify poor prognoses for low grade glioma patients. These results demonstrate that ecPath enables the detection of ecDNA from routinely available H&E imaging alone and help nominate aggressive tumors with ecDNA to study and target it.

pathology↗

bioRxiv2021

The landscape of extrachromosomal circular DNA in medulloblastoma

Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution of drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but the ecDNA landscape and its association with specific MB subgroups, its impact on enhancer rewiring, and its potential clinical implications, are not known. We assembled a retrospective cohort of 468 MB patient samples with available whole genome sequencing (WGS) data covering the four major MB subgroups WNT, SHH, Group 3 and Group 4. Using computational methods for the detection and reconstruction of ecDNA1, we find ecDNA in 82 patients (18%) and observe that ecDNA+ MB patients are more than twice as likely to relapse and three times as likely to die of disease. In addition, we find that individual medulloblastoma tumors often harbor multiple ecDNAs, each containing different amplified oncogenes along with co-amplified non-coding regulatory enhancers. ecDNA was substantially more prevalent among 31 analyzed patient-derived xenograft (PDX) models and cell lines than in our patient cohort. By mapping the accessible chromatin and 3D conformation landscapes of MB tumors that harbor ecDNA, we observe frequent candidate "enhancer rewiring" events that spatially link oncogenes with co-amplified enhancers. Our study reveals the frequency and diversity of ecDNA in a subset of highly aggressive tumors and suggests enhancer rewiring as a frequent oncogenic mechanism of ecDNAs in MB. Further, these results demonstrate that ecDNA is a frequent and potent driver of poor outcome in MB patients.

cancer biology↗