Recent advances in proteomically subtyping pancreatic ductal adenocarcinomas and their potential clinical impact

Roesli, Christoph

doi:10.1586/14789450.2015.983478

Expert Review of Proteomics

2014

DOI: 10.1586/14789450.2015.983478

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Recent advances in proteomically subtyping pancreatic ductal adenocarcinomas and their potential clinical impact

Christoph Roesli

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Cited by 2 publications

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“…A variety of proteomics approaches have been applied in the search for diagnostic or prognostic biomarkers for PDAC, although this work has yet to achieve clinical impact (8). In a recent study, proteomic and phosphoproteomic interrogation of PDAC versus normal tissue via a LC-MS/MS workflow identified several protein kinases exhibiting increased expression in tumor tissue, including HIPK1 and MLCK (9).…”

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Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling

Humphrey

Nagrial

et al. 2016

Molecular & Cellular Proteomics

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Comprehensive characterization of signaling in pancreatic ductal adenocarcinoma (PDAC) promises to enhance our understanding of the molecular aberrations driving this devastating disease, and may identify novel therapeutic targets as well as biomarkers that enable stratification of patients for optimal therapy. Here, we use immunoaffinity-coupled high-resolution mass spectrometry to characterize global tyrosine phosphorylation patterns across two large panels of human PDAC cell lines: the ATCC series (19 cell lines) and TKCC series (17 cell lines). This resulted in the identification and quantification of over 1800 class 1 tyrosine phosphorylation sites and the consistent segregation of both PDAC cell line series into three subtypes with distinct tyrosine phosphorylation profiles. Subtype-selective signaling networks were characterized by identification of subtype-enriched phosphosites together with pathway and network analyses. This revealed that the three subtypes characteristic of the ATCC series were associated with perturbations in signaling networks associated with cell-cell adhesion and epithelial-mesenchyme transition, mRNA metabolism, and receptor tyrosine kinase (RTK) signaling, respectively. Specifically, the third subtype exhibited enhanced tyrosine phosphorylation of multiple RTKs including the EGFR, ERBB3 and MET. Interestingly, a similar RTK-enriched subtype was identified in the TKCC series, and 'classifier' sites for each series identified using Random Forest models were able to predict the subtypes of the alternate series with high accuracy, highlighting the conservation of the three subtypes across the two series. Finally, RTK-enriched cell lines from both series exhibited enhanced sensitivity to the small molecule EGFR inhibitor erlotinib, indicating that their phosphosignature may provide a predictive biomarker for response to this targeted therapy. These studies highlight how resolution of subtype-selective signaling networks can provide a novel taxonomy for particular cancers, and provide insights into PDAC biology that can be exploited for improved patient management. Author contributions: ESH undertook MS-based phosphotyrosine profiling across the ATCC cohort as well as Western blot analyses and erlotinib sensitivity assays for this panel. AMN and MP generated cell lines and subsequent cell lysates for the TKCC cohort, and AMN characterized erlotinib sensitivity across this panel. S-PS undertook phosphotyrosine profiling for the TKCC cohort. GML facilitated tissue culture processes. ESH, FH, LGH, DKC, AVB and RJD contributed to experimental design and project planning. Bioinformatic analyses were primarily undertaken by JW, with bioinformatics contributions and figure generation performed by ESH. ESH, JW and RJD prepared the manuscript, with input from RGP and AY. Overall project coordination was undertaken by RJD. 1 The abbreviations used are: PDAC, pancreatic ductal adenocarci-

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confidence: 99%

Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling

Humphrey

Nagrial

et al. 2016

Molecular & Cellular Proteomics

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Protein biomarkers for early detection of diseases: The decisive contribution of combinatorial peptide ligand libraries

Boschetti¹,

D’Amato

Candiano

et al. 2018

Journal of Proteomics

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Recent advances in proteomically subtyping pancreatic ductal adenocarcinomas and their potential clinical impact

Cited by 2 publications

References 24 publications

Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling

Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling

Protein biomarkers for early detection of diseases: The decisive contribution of combinatorial peptide ligand libraries

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