Proteomic Characterization of Intrahepatic Cholangiocarcinoma Identifies Distinct Subgroups and Proteins Associated with Time-To-Recurrence

Werner, T.; Budau, K.-L.; Cosenza Contreras, M.; Hause, F.; Kurowski, K.; Pinter, N.; Schueler, J.; Werner, M.; Sigel, C.; Tang, L.; Bronsert, P.; Schilling, O.

doi:10.1101/2024.02.28.582093

bioRxiv · 10.1101/2024.02.28.582093

Proteomic Characterization of Intrahepatic Cholangiocarcinoma Identifies Distinct Subgroups and Proteins Associated with Time-To-Recurrence

Werner, T.·Budau, K.-L.·Cosenza Contreras, M.·Hause, F.·Kurowski, K.·Pinter, N.·Schueler, J.·Werner, M.·Sigel, C.·Tang, L.·Bronsert, P.·Schilling, O.

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Abstract

Background & AimsIntrahepatic cholangiocarcinoma (ICC) is a poorly understood cancer with dismal survival and high recurrence rates. ICCs are often detected in advanced stages. Surgical resection is the most important first-line treatment but limited to non-advanced cases, whereas chemotherapy provides only a moderate benefit. The proteome biology of ICC has only been scarcely studied and the prognostic value of initial ICCs proteomic features for the time-to-recurrence (TTR) remains unclear. MethodsWe dissected formalin-fixed, paraffin-embedded samples from 80 tumor- and 77 matching adjacent non-malignant (TANM) tissues. All samples were measured via liquid-chromatography mass-spectrometry (LC-MS/MS) in data independent acquisition mode (DIA). ResultsTumor- and TANM tissue showed strongly different biologies and DNA-repair, translation, and matrisomal processes were upregulated in ICC. In a hierarchical clustering analysis, we determined two proteomic subgroups of ICC, which showed significantly diverging TTRs. Cluster 1, which is associated with a beneficial prognosis, was enriched for matrisomal processes and proteolytic processing, while cluster 2 showed increased RNA and protein turnover. In a second, independent Cox proportional hazards model analysis, we identified individual proteins whose expression correlates with TTR distribution. Proteins with a positive hazard ratio were mainly involved in carbon/glucose metabolism and protein turnover. Conversely, proteins associated with a low hazard ratio were mostly linked to the extracellular matrix. Additional proteome profiling of patient-derived xenograft tumor models of ICC successfully distinguished tumor and stromal proteins and provided insights into cell-matrix interactions. ConclusionsWe successfully determine the proteome biology of ICC and present two proteome clusters in ICC patients with significantly different TTR rates and distinct biological motifs. A xenograft model confirmed the importance of tumor-stroma interactions for this cancer.

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Werner, T., Budau, K.-L., Cosenza Contreras, M., Hause, F., Kurowski, K., Pinter, N., Schueler, J., Werner, M., Sigel, C., Tang, L., Bronsert, P., Schilling, O.. 2024-02-29. Proteomic Characterization of Intrahepatic Cholangiocarcinoma Identifies Distinct Subgroups and Proteins Associated with Time-To-Recurrence. https://doi.org/10.1101/2024.02.28.582093

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