Oncogenic KRAS induces a massive reprogramming of the epithelial cell surface during malignant transformation
(2017) 32nd Scientific Day of the Department of Pathology and Cell Biology — Location: Montréal (Canada) (28.March.2017)
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- Authors
Aubert, Léo 
- Abstract
- Introduction: KRAS is frequently mutated in human cancers, including ~45% of colorectal adenocarcinoma (CRC). Despite continuous efforts, oncogenic KRAS is still deemed “undruggable”, warranting the need for alternative therapeutic approaches. While oncogenic KRAS is described to regulate many intracellular signaling events that are currently being evaluated as potential therapeutic targets, much less is known about its potential impact on the cell surface. Elucidating how oncogenic KRAS modifies the cell surface proteome (surfaceome) could help understand its complex mechanism of action, and possibly identify new “druggable” targets and/or tumor-specific biomarkers. Methods and results: Herein, we have optimized a cutting-edge chemoproteomic approach based on the labeling of cell surface proteins with biotin reagents, their subsequent purification with avidin chromatography, and quantification using label-free quantitative proteomics with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Using an intestinal crypt epithelial cell model that reflects KRAS-induced malignant transformation, our LC-MS/MS analyses allowed the identification of over 350 cell surface molecules from which 13% and 22% were significantly upregulated and downregulated in KRAS-transformed cells, respectively. Thus, we found that oncogenic KRAS modulates the surface expression of a large network of proteins. Interestingly, while many of these changes are associated with a KRAS-dependent gene expression signature, we also identified numerous surface proteins that appear to be regulated in a transcription-independent manner. Conclusion and relevance: Taken together, these results indicate that oncogenic KRAS leads to a massive reprogramming of the epithelial cell surface, and suggest multiple cell surface proteins as molecular targets or diagnostic markers for KRAS-dependent cancers.
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Citations
Aubert, L., Nandagopal, N., Nourreddine, S., Lavoie, G., Angers, S., & Roux, P. P. (2017). Oncogenic KRAS induces a massive reprogramming of the epithelial cell surface during malignant transformation. 32nd Scientific Day of the Department of Pathology and Cell Biology, Montréal (Canada). https://hdl.handle.net/2078.5/28939