# Conserved Phosphoprotein Networks Identify Actionable Adhesion/Wnt and Metallothionein Modules in Cholangiocarcinoma

## TL;DR

This study identifies key signaling pathways in cholangiocarcinoma by analyzing phosphoprotein patterns across tumor regions and patients.

## Contribution

The study discovers conserved phosphoprotein modules related to adhesion/Wnt and metallothionein pathways in cholangiocarcinoma.

## Key findings

- Two conserved signaling modules were identified: adhesion/Wnt axis and metallothionein modules.
- Hyperphosphorylated CTNNB1 (β-catenin) and MT1G/MT2A proteins are central to these modules.
- Pathways like focal adhesion and cytoskeletal modulation are highlighted as critical activities.

## Abstract

Background/Objectives: Cholangiocarcinoma (CCA) is a very aggressive biliary carcinoma characterised by significant molecular heterogeneity and restricted treatment alternatives. Despite genomic and proteomic investigations revealing recurrent changes, the signalling dynamics influencing tumour behaviour remain inadequately comprehended. Methods: We conducted high-resolution Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS)-based phosphoproteomics on paired tumour and surrounding tissues from 13 CCA patients in Northeast Thailand, meticulously sampling four geographically unique tumour areas for each patient. Our analysis concentrated on phosphoproteins consistently identified across all regions, delineating strong tumour-specific and cohort-wide phosphorylation signatures. Results: Notwithstanding considerable inter-patient variability, two conserved signalling modules were identified: an adhesion/Wnt axis regulated by hyperphosphorylated CTNNB1 protein (β-catenin) and a metal-handling module facilitated by metallothionein-1G (MT1G) protein and metallothionein-2A (MT2A) protein. Pathway enrichment identified focal adhesion, ECM-receptor interaction, cytoskeletal modulation, and mineral absorption as critical activities. Conclusions: This study elucidates conserved oncogenic pathways by analysing phosphoproteomic signatures across regional and patient-level variability, emphasising phosphoproteomics as a robust framework for biomarker and therapeutic development in CCA.