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<p>Intrahepatic cholangiocarcinoma (ICC) features poor survival due to frequent recurrences and limited prognostic markers. Using mass spectrometry-based proteomics, we analyze two independent cohorts comprising 80 and 62 treatment-naive ICC tumors, along with 9 independent patient-derived xenografts (PDX). In the first cohort, we identify two subclusters with distinct times-to-recurrence (TTR): An extracellular matrix (ECM)-enriched cluster (mean TTR 859 days) and a proliferation cluster (mean TTR 229 days). A 4-protein classifier trained on our cohort accurately stratifies these clusters in the Dong et al. dataset (2022) and in our second cohort, revealing similar proteomic motifs and clinical outcomes. The translation regulator EIF4A1, enriched in ICCs of both clusters, emerges as a therapeutic target, as its inhibition with eFT226 significantly reduces tumor growth in an ICC PDX model. Proteomic analyses of various PDX models also emphasize the critical role of tumor-stroma interactions in ICC. Overall, this study establishes two prognostic proteomic clusters, validates their relevance across datasets, and highlights EIF4A1 inhibition as a potential therapeutic strategy.</p>

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Proteomic characterization of intrahepatic cholangiocarcinoma identifies risk-stratifying subgroups and EIF4A1 as a therapeutic target

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Tilman Werner,
  • Johanna Thiery,
  • Klara-Luisa Budau,
  • Annika Topitsch,
  • Miguel Cosenza-Contreras,
  • Niko Pinter,
  • Frank Hause,
  • Julius Rühlmann,
  • Gaia Gentile,
  • Jannis Heyer,
  • Konrad Kurowski,
  • Julia Schüler,
  • Philipp Anton Holzner,
  • Martin Werner,
  • Carlie Sigel,
  • Laura H. Tang,
  • Peter Bronsert,
  • Oliver Schilling

摘要

Intrahepatic cholangiocarcinoma (ICC) features poor survival due to frequent recurrences and limited prognostic markers. Using mass spectrometry-based proteomics, we analyze two independent cohorts comprising 80 and 62 treatment-naive ICC tumors, along with 9 independent patient-derived xenografts (PDX). In the first cohort, we identify two subclusters with distinct times-to-recurrence (TTR): An extracellular matrix (ECM)-enriched cluster (mean TTR 859 days) and a proliferation cluster (mean TTR 229 days). A 4-protein classifier trained on our cohort accurately stratifies these clusters in the Dong et al. dataset (2022) and in our second cohort, revealing similar proteomic motifs and clinical outcomes. The translation regulator EIF4A1, enriched in ICCs of both clusters, emerges as a therapeutic target, as its inhibition with eFT226 significantly reduces tumor growth in an ICC PDX model. Proteomic analyses of various PDX models also emphasize the critical role of tumor-stroma interactions in ICC. Overall, this study establishes two prognostic proteomic clusters, validates their relevance across datasets, and highlights EIF4A1 inhibition as a potential therapeutic strategy.