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

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE
    • Publication Information:
      Publication: Limerick : Elsevier Science Ireland
      Original Publication: Amsterdam, Elsevier/North-Holland.
    • Subject Terms:
      Urinary Bladder Neoplasms*/drug therapy ; Urinary Bladder Neoplasms*/genetics ; Urinary Bladder Neoplasms*/pathology ; Urinary Bladder Neoplasms*/mortality ; Drug Resistance, Neoplasm*/genetics ; Gemcitabine* ; Deoxycytidine*/analogs & derivatives ; Deoxycytidine*/pharmacology ; Deoxycytidine*/therapeutic use; Humans ; Cell Movement/drug effects ; Male ; Female ; Cancer-Associated Fibroblasts/metabolism ; Cancer-Associated Fibroblasts/drug effects ; Cancer-Associated Fibroblasts/pathology ; BCG Vaccine/therapeutic use ; Prognosis ; Aged ; Cell Line, Tumor ; Middle Aged ; Neoplasm Invasiveness ; Gene Expression Regulation, Neoplastic ; Non-Muscle Invasive Bladder Neoplasms
    • 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.
      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.)
    • Contributed Indexing:
      Keywords: Alternative chemotherapy; Cancer-associated fibroblast; Chemoresistance-motility signature; Immunotherapy; Non-muscle-invasive bladder cancer; Stepwise molecular evolution
    • Accession Number:
      0 (Gemcitabine)
      0W860991D6 (Deoxycytidine)
      0 (BCG Vaccine)
    • Publication Date:
      Date Created: 20241128 Date Completed: 20241208 Latest Revision: 20241208
    • Publication Date:
      20241210
    • Accession Number:
      10.1016/j.canlet.2024.217339
    • Accession Number:
      39608442