GEO series

PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma [Cut&Run]

GSE253893 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 28 samples Submitted 2025/04/03 Platform GPL30173

Summary

Alveolar rhabdomyosarcoma (ARMS) patients harboring PAX3-FOXO1 and PAX7-FOXO1 fusion proteins exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we develop a muscle progenitor model and use epigenomic approaches to unravel genome rewiring events mediated by PAX3/7 fusion proteins. Among the key targets of PAX3/7 fusion proteins, we identify a cohort of oncogenes, FGF receptors, tRNA-modifying enzymes, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.

Published in

PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma

Kalita B, Martinez-Cebrian G, McEvoy J et al. · Cell 2025 · PMID 40185100 · doi:10.1016/j.cell.2025.03.008

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Direct links to NCBI, no account and no request form: the whole study as GSE253893_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 28 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1067632 and SRA study SRP485230. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 40185100) ↗

Study design

14 conditions, mostly in duplicate

Control_H3K4me1 ×2 P3F1_H3K4me1 ×2 P7F1_H3K4me1 ×2 Control_H3K4me3 ×2 P3F1_H3K4me3 ×2 P7F1_H3K4me3 ×2 Control_H3K27ac ×2 P3F1_H3K27ac ×2 +6 more

Supports a between-group comparison across 28 samples.

14 replicated groups read from 28 sample titles; they account for 28 of them. Check it against the sample list below before relying on it.

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