ArticleEBioMedicine2026
Somatic structural variants drive upper tract urothelial carcinoma muscle invasiveness via activation of TPX2 transcription.
Article in EBioMedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundUpper tract urothelial carcinoma (UTUC) is an uncommon but aggressive malignancy. Muscle invasion is strongly associated with poor prognosis and limited treatment options. Revealing the molecular basis of muscle invasiveness in UTUC is crucial.
methodsWe characterised somatic structural variants (SSVs) from 162 patients with UTUC and integrated these data with bulk RNA-seq, single cell RNA-seq and spatial transcriptomics, with selected SSVs validated by single-molecule sequencing. Furthermore, functional validation experiments, including dual-luciferase reporter assays, wound healing, and invasion/migration assays, were conducted on both the SSV region upstream of TPX2 and the TPX2 gene itself in the 5637 cell line.
findingsWe found that SSVs were enriched in muscle-invasive (MI) -UTUC compared with non-muscle-invasive (NMI)-UTUC, and were associated with gene expression changes independent of copy-number variation. TPX2 emerged as a representative target, with TPX2-associated SSVs linked to TPX2 over expression and patient poorer progression-free and overall survival. Functional study indicated that a TPX2-upstream SSV region enhances TPX2 expression through promoter regulation, leading to increased invasiveness of 5637 cells. Single cell analyses revealed that TPX2-positive cycling epithelial cells exhibited heightened proliferative signalling and distinct ligand-receptor interactions, particularly involving EGFR- and EPHA2-related pathways. Spatial transcriptomics further localised TPX2-positive spots to epithelial mesenchymal transition (EMT) -enriched neighbourhoods with elevated EGFR/EPHA2 associated ligands, and showed markedly higher abundance in MI-UTUC.
interpretationSSVs drive transcriptional reprogramming, disease aggressiveness and microenvironmental remodelling in UTUC. The signatures of SSVs could classify UTUC into classes with different prognosis. Furthermore, SSVs of TPX2 might be a potential biomarker and candidate therapeutic vulnerability.
fundingStated in acknowledgements section of manuscript.
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