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Introduction <p>Mechanism underlying resistance to enfortumab vedotin (EV) and prognostication of Nectin-4 expression in muscle-invasive bladder cancer (MIBC) remains unclear.</p> Methods <p>We generated gemcitabine-resistant HT-1376 and cisplatin-resistant HT-1376 cells generated from parental HT1376 cells (derived from MIBC). Transcriptome analysis was conducted to explore the biological function of differentially expressed genes detected in chemoresistant HT-1376 cells compared to parental HT-1376. In 70 patients with MIBC undergoing radical cystectomy, unsupervised hierarchical clustering was performed using immunohistochemical staining pattern with GATA3, KRT20, KRT5/6, KRT14, and Nectin-4 expression derived from the gene expression–based Nectin-4-modified NanoString molecular classification: Luminal-Nec4-High, Luminal-Nec4-Low, Basal-Nec4-High, and Basal-Nec4-Low subgroups.</p> Results <p>We found significant downregulation of Nectin-4 expression along with epithelial-to-mesenchymal transition in chemoresistant HT-1376 cells. Exogenous expression of <i>NECTIN4</i> in chemoresistant HT-1376 cells partially restored sensitivity to EV. RNA seq identified differentially expressed genes, including Nectin-4 and small proline-rich proteins, downregulated in chemoresistant HT-1376 cells. Over-representation analysis using GO and KEGG revealed upregulation of gene sets enriched for ribosome biogenesis–related pathways in chemoresistant HT-1376 cells. Nectin-4-modified molecular subtype resulted in better stratification of survival—the Luminal-Nec4-High subgroup had the best and the Basal-Nec4-Low subgroup had the worst prognosis. Comparing molecular subtypes of MIBC cells between transurethral resection specimens and matched radical cystectomy specimens revealed that 43% of neoadjuvant chemotherapy–treated patients with luminal subtype tumors showed a marked shift to the basal subtype in the cystectomy specimens.</p> Conclusion <p>The clinical utility of Nection-4, associated molecules, and Nectin-4-modified molecular subtype need to be studied for better management strategies for MIBC.</p>

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Clinical relevance of Nectin-4 downregulation and biological changes caused by cytotoxic chemotherapy in bladder cancer

  • 期刊论文

  • 发表日期：

    2025年6月25日

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  • Makito Miyake,
  • Takuya Owari,
  • Kota Iida,
  • Sayuri Onishi,
  • Nobutaka Nishimura,
  • Tomomi Fujii,
  • Cynthia N. Jinno,
  • Hideki Furuya,
  • Yuki Oda,
  • Tatsuki Miyamoto,
  • Mitsuru Tomizawa,
  • Takuto Shimizu,
  • Kenta Onishi,
  • Shunta Hori,
  • Yosuke Morizawa,
  • Daisuke Goto,
  • Yasushi Nakai,
  • Nobumichi Tanaka,
  • Noriyoshi Miura,
  • Tadahiko Kikugawa,
  • Takashi Saika,
  • Charles Rosser,
  • Kiyohide Fujimoto

摘要

Introduction

Mechanism underlying resistance to enfortumab vedotin (EV) and prognostication of Nectin-4 expression in muscle-invasive bladder cancer (MIBC) remains unclear.

Methods

We generated gemcitabine-resistant HT-1376 and cisplatin-resistant HT-1376 cells generated from parental HT1376 cells (derived from MIBC). Transcriptome analysis was conducted to explore the biological function of differentially expressed genes detected in chemoresistant HT-1376 cells compared to parental HT-1376. In 70 patients with MIBC undergoing radical cystectomy, unsupervised hierarchical clustering was performed using immunohistochemical staining pattern with GATA3, KRT20, KRT5/6, KRT14, and Nectin-4 expression derived from the gene expression–based Nectin-4-modified NanoString molecular classification: Luminal-Nec4-High, Luminal-Nec4-Low, Basal-Nec4-High, and Basal-Nec4-Low subgroups.

Results

We found significant downregulation of Nectin-4 expression along with epithelial-to-mesenchymal transition in chemoresistant HT-1376 cells. Exogenous expression of NECTIN4 in chemoresistant HT-1376 cells partially restored sensitivity to EV. RNA seq identified differentially expressed genes, including Nectin-4 and small proline-rich proteins, downregulated in chemoresistant HT-1376 cells. Over-representation analysis using GO and KEGG revealed upregulation of gene sets enriched for ribosome biogenesis–related pathways in chemoresistant HT-1376 cells. Nectin-4-modified molecular subtype resulted in better stratification of survival—the Luminal-Nec4-High subgroup had the best and the Basal-Nec4-Low subgroup had the worst prognosis. Comparing molecular subtypes of MIBC cells between transurethral resection specimens and matched radical cystectomy specimens revealed that 43% of neoadjuvant chemotherapy–treated patients with luminal subtype tumors showed a marked shift to the basal subtype in the cystectomy specimens.

Conclusion

The clinical utility of Nection-4, associated molecules, and Nectin-4-modified molecular subtype need to be studied for better management strategies for MIBC.