Faculty, Staff and Student Publications

Publication Date

2-1-2025

Journal

Cancer Letters

DOI

10.3350/cmh.2024.0333

PMID

39038962

PMCID

PMC11540371

PubMedCentral® Posted Date

7-23-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature confirmed interaction with cancer-associated fibroblasts (CAFs). The high-CrM groups mainly included NMIBC patients with poor prognosis (progression-free survival analysis by log-rank test based on UROMOL cohort, p < 0.001), T1-high grade, high European Association of Urology (EAU) risk score, and also included MIBC patients with a history of metastases. Additionally, relative ineffectiveness was observed for BCG (the chi-square test based on BRS cohort, p = 0.02) and immune checkpoint inhibitors (ICIs) in patients with high-CrM. In addition, we identified five drugs that can be used with gemcitabine in these patients, including doxorubicin, docetaxel, paclitaxel, napabucacin, and valrubicin, and verified their efficacy. This study provides insights into NMIBC progression to MIBC via molecular evolution. The CrM signature can assess NMIBC prognosis and BCG treatment response, suggesting alternative treatments. Furthermore, these results need to be prospectively validated.

Keywords

Humans, Urinary Bladder Neoplasms, Drug Resistance, Neoplasm, Gemcitabine, Deoxycytidine, Cell Movement, Male, Female, Cancer-Associated Fibroblasts, BCG Vaccine, Prognosis, Aged, Cell Line, Tumor, Middle Aged, Neoplasm Invasiveness, Gene Expression Regulation, Neoplastic, Non-Muscle Invasive Bladder Neoplasms

Comments

This article has been corrected. See Clin Mol Hepatol. 2025 Feb 27;31(2):669.

Published Open-Access

yes

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