Abstract
Background & Aims Intrahepatic 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 ICC’s proteomic features for the time-to-recurrence (TTR) remains unclear.
Methods We 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).
Results Tumor– 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.
Conclusions We 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.
Competing Interest Statement
The authors have declared no competing interest.
5 Abbreviations
- AAALAC
- Association for Assessment and Accreditation of Laboratory Animal Care International
- AJCC
- American Joint Committee on Cancer
- BCA
- Bicinchonic Acid
- BGN
- Biglycan
- CCA
- Cholangiocarcinoma
- COL3A1
- Collagen alpha-1(III) chain
- CPHM
- Cox’ Proportional Hazards Model
- CPTAC
- Clinical Proteomic Tumor Analysis Consortium
- DIA
- Data Independent Acquisition
- DNA
- Desoxyribonucleic acid
- ECM
- Extracellular Matrix
- FBN1
- Fibrillin-1
- FDR
- False Discovery Rate
- FFPE
- Formalin-fixed, Paraffin-embedded
- FU-ICC
- Fudan University Intrahepatic Cholangiocarcinoma Cohort
- FUS
- Oncogene FUS
- GGT5
- Glutathione Hydrolase 5
- GV-SOLAS
- Gesellschaft für Versuchstierkunde – Society for Laboratory Animal Science
- H1-0
- Histone 1.0
- HAT
- Highly Actionable Targets
- HCD
- Higher-energy Collisional Dissociation
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic Acid
- HPLC
- High-performance Liquid Chromatography
- ICC
- Intrahepatic Cholangiocarcinoma
- IDH1/2
- cytoplasmic and mitochondrial isocitrate dehydrogenase 1 and 2
- iRTs
- Indexed Retention Time Standards
- ITIH2
- Inter-alpha-trypsin inhibitor heavy chain H2
- LC-MS/MS
- Liquid-chromatography mass spectrometry
- LDHA
- L-lactate dehydrogenase A chain
- LFQ
- Label-free Quantitation
- LUM
- Lumican
- MSKCC
- Memorial Sloan Kettering Cancer Center New York
- PARP1
- Poly-[ADP-ribose]-polymerase 1
- PCA
- Principal Component Analysis
- PDX
- Patient-derived Xenograft
- PLS
- Partial Least Squares
- PRELP
- Prolargin
- PSMB4
- Proteasome subunit beta type-4
- SDS
- Sodiumdodecylsulfate
- SKI
- SKI oncoprotein
- TANM
- Tumor-adjacent, non-malignant
- TEAB
- Tetraethylammonium Bromide
- TNS-1
- Tensin 1
- TTR
- Time to Recurrence
- UICC
- Union for International Cancer Control
- VTN
- Vitronectin