Biology subjects

Wong-Erasmus, M.

Publications and source records attributed to Wong-Erasmus, M..

4 recordsLinked to original sources

bioRxiv2026

METTL1 gene dosage and catalytic activity define a targetable vulnerability in pediatric cancers

METTL1 is responsible for catalyzing N7-methylguanosine (m7G) methylation of tRNAs. METTL1-dependent oncogenic mechanisms include both its methyltransferase catalytic activity and, in specific instances, non-catalytic interactions that maintain aminoacylated tRNA levels in malignant cells. We show that METTL1 copy number gain and elevated expression are a feature of pediatric tumors that are METTL1 dependent, using Cas13-mediated RNA to reduce the threshold of METTL1 mRNA and protein, which disrupts both catalytic and non-catalytic functions. In cell lines with METTL1 gene amplification, specific degradation of METTL1 mRNA impaired colony formation, triggered cell death, and decreased the translation efficiency of a subset of genes enriched for codons decoded m7G-modified tRNAs. METTL1 inhibition was accompanied by downregulation of c-MYC, n-MYC and MCL-1 protein expression. METTL1 silencing synergizes with drugs targeting anti-apoptotic members of the BCL2 family, notably BCL-xL. Importantly, the catalytic activity of METTL1 was required to rescue cells from the deleterious consequences of METTL1 silencing. We conclude that inhibiting the catalytic activity of METTL1 has potential therapeutic efficacy, particularly in tumors with METTL1 amplification. Synergistic combinations with BH3-mimetic drugs may be a promising therapeutic combination.

cancer biology↗

bioRxiv2026

Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma

Purpose: Treatment for children with high-risk neuroblastoma relies on conventional chemotherapy and anti-GD2 immunotherapy. However, 5-year survival is only 50%, with high rates of late effects. Targeted therapy combinations are a major priority for these patients. The BCL2 inhibitor venetoclax, in combination with cyclophosphamide/topotecan, has clinical activity in relapsed and refractory neuroblastoma. We sought more effective and safer venetoclax combinations through systematic preclinical testing. Experimental design: Synergistic combinations were identified by high-throughput screening using patient-derived xenograft (PDX) models and confirmed in vivo. The leading combination (venetoclax-alisertib) was compared to combination chemotherapy in a clinical trial-like study using 22 PDX models, in scheduling experiments designed to reduce short-term toxicity, and in combination with anti-GD2 immunotherapy. BCL2 and Bim-BCL2 complex protein levels were assessed as predictors of sensitivity. Results: In vitro synergy with venetoclax was observed for standard-of-care chemotherapies and targeted agents, including DNA topoisomerase, microtubule, HDAC and Aurora kinase A (AURKA) inhibitors. Venetoclax-alisertib was particularly effective in vivo. In an n=1 study, venetoclax-alisertib induced objective response in all models. Activity was most striking in models of MYCN-amplified disease (n=12), doubling median survival time compared to cyclophosphamide/topotecan, and outperforming venetoclax-cyclophosphamide-topotecan. Efficacy was maintained with discontinuous schedules, minimizing hematological toxicity without substantially compromising activity. PDX-engrafted animals treated with venetoclax-alisertib and anti-GD2 immunotherapy survived tumor-free long-term. BCL2 expression and BCL2-Bim complex levels were of limited value for predicting response. Conclusion: Our findings support advancement of BCL2-AURKA inhibition to clinical trial for neuroblastoma with or without anti-GD2 immunotherapy, particularly in patients with MYCN amplified disease.

cancer biology↗

bioRxiv2025

Single-cell RNA-sequencing of cerebral spinal fluid identifies circulating tumour cells in children with brain cancer

Paediatric central nervous system (CNS) tumours are the leading cause of cancer-related death in children, yet disease monitoring remains challenging. Conventional approaches, including imaging and cytology, lack sensitivity, delaying intervention. Liquid biopsy offers a minimally invasive alternative, but the utility of circulating tumour cells (CTCs) in paediatric CNS tumours as biomarkers is poorly defined. We developed a CTC detection and characterisation workflow from cerebrospinal fluid (CSF) utilising single-cell RNA-sequencing (scRNA-seq) and applied this to ten CNS tumour subtypes in 16 patients. CTCs were identified in all cases, with higher burdens in pineoblastoma, medulloblastoma and atypical teratoid rhabdoid tumours. Longitudinal profiling revealed CTC dynamics correlated with clinical disease course and anticipated relapse. Critically, scRNA-seq uncovered a sub-clonal canonical driver alteration at diagnosis that only became detectable by bulk RNA-seq at progression, underscoring its potential to resolve clonal dynamics. This workflow enables real-time molecular profiling, offering a transformative strategy for disease monitoring and personalised therapy in paediatric brain tumours.

cancer biology↗

bioRxiv2023

CRUX, a platform for visualising, exploring and analysing cancer genome cohort data

To better understand how tumours develop, identify prognostic biomarkers, and find new treatments, researchers have generated vast catalogues of cancer genome data. However, these datasets are complex so interpreting their important features requires specialized computational skills and analytical tools, which presents a significant technical challenge. To address this, we developed CRUX, a platform for exploring genomic data from cancer cohorts. CRUX enables researchers to perform common analyses including cohort comparisons, biomarker discovery, survival analysis, and create visualisations including oncoplots and lollipop charts. CRUX simplifies cancer genome analysis in several ways: (1) it has an easy-to-use graphical interface; (2) it enables users to create custom cohorts, as well as analyse precompiled public and private user-created datasets; (3) it allows analyses to be run locally to address data privacy concerns (though an online version is also available); and (4) it makes it easy to use additional specialized tools by exporting data in the correct formats. We showcase CRUXs capabilities with case studies employing different types of cancer genome analysis, demonstrating how it can be used flexibly to generate valuable insights into cancer biology. CRUX is freely available at https://github.com/CCICB/CRUX and https://ccicb.shinyapps.io/crux (DOI: 10.5281/zenodo.8015714).

bioinformatics↗