In Vivo SILAC-Based Proteomics Reveals Phosphoproteome Changes during Mouse Skin Carcinogenesis

Sara Zanivan,Alexander Meves,Kristina Behrendt,Erwin M Schoof,Lisa J Neilson,Jürgen Cox,Hao R Tang,Gabriela Kalna,Janine H Van Ree,Jan M Van Deursen,Carol S Trempus,Laura M Machesky,Rune Linding,Sara A Wickström,Reinhard Fässler,Matthias Mann

doi:10.1016/j.celrep.2013.01.003

Abstract

Cancer progresses through distinct stages, and mouse models recapitulating traits of this progression are frequently used to explore genetic, morphological, and pharmacological aspects of tumor development. To complement genomic investigations of this process, we here quantify phosphoproteomic changes in skin cancer development using the SILAC mouse technology coupled to high-resolution mass spectrometry. We distill protein expression signatures from our data that distinguish between skin cancer stages. A distinct phosphoproteome of the two stages of cancer progression is identified that correlates with perturbed cell growth and implicates cell adhesion as a major driver of malignancy. Importantly, integrated analysis of phosphoproteomic data and prediction of kinase activity revealed PAK4-PKC/SRC network to be highly deregulated in SCC but not in papilloma. This detailed molecular picture, both at the proteome and phosphoproteome level, will prove useful for the study of mechanisms of tumor progression.

Highlights

Mouse models of cancer are a resource of great potential in cancer research and they have provided important insights into tumor biology (Marcotte and Muller, 2008; Walrath et al, 2010)
To complement genomic investigations of this process, we here quantify phosphoproteomic changes in skin cancer development using the SILAC mouse technology coupled to high-resolution mass spectrometry
Integrated analysis of phosphoproteomic data and prediction of kinase activity revealed PAK4PKC/SRC network to be highly deregulated in squamous cell carcinoma (SCC) but not in papilloma

Summary

Introduction

Mouse models of cancer are a resource of great potential in cancer research and they have provided important insights into tumor biology (Marcotte and Muller, 2008; Walrath et al, 2010). They have helped in confirming gene function, identifying tumor markers, and contributing to a better understanding of the cellular and molecular mechanisms of tumor initiation and the multistage processes of tumorigenesis. While this has been a central aim of the proteomics community, daunting technological challenges have so far prevented proteomics from complementing the ubiquitous genomic technologies at a similar level of comprehensiveness (Hanash and Taguchi, 2010; Harsha and Pandey, 2010; Pawson and Scott, 2005)

Results

Discussion

Conclusion