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

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

  • Cancer Lett. 2025 Feb 1:610:217339. doi: 10.1016/j.canlet.2024.217339.
Mi-So Jeong 1,  Seung-Woo Baek 2,  Gi-Eun Yang 3,  Jeong-Yeon Mun 4,  Jeong Ah Kim 5,  Tae-Nam Kim 6,  Jong-Kil Nam 7,  Yung-Hyun Choi 8,  Ju-Seog Lee 9,  In-Sun Chu 10,  Sun-Hee Leem 11
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, South Korea.
  • 2 Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South Korea.
  • 3 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.
  • 4 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.
  • 5 Center for Scientific Instrumentation, Korea Basic Science Institute, Chungbuk, 28119, South Korea.
  • 6 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.
  • 7 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.
  • 8 Department of Biochemistry, College of Oriental Medicine, Anti-Aging Research Center, Dong-eui University, Busan, 47227, South Korea.
  • 9 Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA.
  • 10 Bioneer Corporation, Daejeon, 34013, South Korea.
  • 11 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.
PMID: 39608442 DOI: 10.1016/j.canlet.2024.217339
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

Alternative chemotherapy; Cancer-associated fibroblast; Chemoresistance-motility signature; Immunotherapy; Non-muscle-invasive bladder cancer; Stepwise molecular evolution.

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