Dysregulated Mitochondrial Energy Metabolism Drives the Progression of Mucosal Field Effects to Invasive Bladder Cancer

Authors

Sangkyou Lee
Sung Yun Jung
Pawel Kuś
Jolanta Bondaruk
June Goo Lee
Roman Jaksik
Nagireddy Putluri
Khanh N Dinh
David Cogdell
Huiqin Chen
Yishan Wang
Jiansong Chen
Neema Navai
Colin Dinney
Cathy Mendelsohn
David McConkey
Richard R Behringer
Charles C Guo
Peng Wei
Marek Kimmel
Bogdan Czerniak

Language

English

Publication Date

11-1-2025

Journal

The Journal of Pathology

DOI

10.1002/path.6474

PMID

40996337

PMCID

PMC12531120

PubMedCentral® Posted Date

9-25-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Multiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from field effects. Analysis of the mutational landscape identified three types of mutations, referred to as α, β, and γ. Time modeling of the mutations revealed that carcinogenesis may span 30 years and can be divided into dormant and progressive phases. The α mutations developed in the dormant phase. The progressive phase lasted 5 years and was signified by expanding β mutations, but it was driven to invasive cancer by γ mutations. The mutational landscape emerged on a background of disorganized urothelial differentiation, activated epithelial-mesenchymal transition, and enhanced immune infiltration with T-cell exhaustion. Complex dysregulation of mitochondrial energy metabolism with downregulation of oxidative phosphorylation emerged as the leading mechanism driving the progression of mucosal field effects to invasive cancer. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords

Humans, Disease Progression, Energy Metabolism, Epithelial-Mesenchymal Transition, Mitochondria, Mutation, Neoplasm Invasiveness, Urinary Bladder Neoplasms, bladder cancer, mutational landscape, time modeling, dysregulation of mitochondrial energy metabolism

Published Open-Access

yes

Recommended Citation

Lee, Sangkyou; Jung, Sung Yun; Kuś, Pawel; et al., "Dysregulated Mitochondrial Energy Metabolism Drives the Progression of Mucosal Field Effects to Invasive Bladder Cancer" (2025). Faculty and Staff Publications. 4895.
https://digitalcommons.library.tmc.edu/baylor_docs/4895