Chemoresistance-motility signature of molecular evolution to chemotherapy in non-muscle-invasive bladder cancer and its clinical implications.

Autor: Jeong MS; Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, South Korea., Baek SW; Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South Korea., Yang GE; Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Department of Health Sciences, The Graduated of Dong-A University, Busan, 49315, South Korea., Mun JY; Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA., Kim JA; Center for Scientific Instrumentation, Korea Basic Science Institute, Chungbuk, 28119, South Korea., Kim TN; Department of Urology, Pusan National University Hospital, Pusan National University School of Medicine, Biomedical Research Institute and Pusan National University Hospital, Busan, 49241, South Korea., Nam JK; Department of Urology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, 50612, South Korea., Choi YH; Department of Biochemistry, College of Oriental Medicine, Anti-Aging Research Center, Dong-eui University, Busan, 47227, South Korea., Lee JS; Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA., Chu IS; Bioneer Corporation, Daejeon, 34013, South Korea., Leem SH; Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Department of Health Sciences, The Graduated of Dong-A University, Busan, 49315, South Korea. Electronic address: shleem@dau.ac.kr.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2025 Feb 01; Vol. 610, pp. 217339. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1016/j.canlet.2024.217339
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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