Colorectal cancer (CRC) arises as a result of accumulated mutations in key proteins that regulate cell proliferation, differentiation and death. Large scale sequencing studies have established the predominance of mutations in proteins involved in Wnt signaling pathway in a large number of CRC patients. It was also shown that over 90% of sporadic CRC cases, harboured mutation in APC and/or β-catenin gene both of which are involved in Wnt signaling pathway. One of the proposed mechanisms of intercellular signaling involves exosomes which act as messengers carrying oncoproteins from malignant to non-malignant target cells. In this study, an integrative proteogenomic analysis identified the presence of mutated β-catenin in exosomes secreted by CRC cells. Follow up cell-based and mouse experiments established that exosomes released from LIM1215 CRC cells stimulated Wnt signaling pathway in a variety of recipient cells in the tumor microenvironment. Additionally, exosomes derived from LIM1215 cells promoted proliferation in the recipient cells. SILAC-based quantitative proteomics analysis confirmed the transfer of mutant β-catenin to the nucleus of the recipient cells. To understand the role of exosomes in the tumor microenvironment, variety of cells including NK, T, cancer associated fibroblasts, endothelial, monocytes and pericytes were treated with exosomes and analysed by quantitative proteomics and phosphoproteomics. Even though the same exosomes were used, the analysis highlighted the activation of different signaling pathways based on the recipient cell type. Interestingly, cancer cell-derived exosomes also altered the soluble secreted proteins profiles of the stromal cells in the tumor microenvironment thus reprogramming the tumor niche in favour of cancer progression. This unpublished study unravelled many novel roles of exosomes bearing mutant β-catenin in context of Wnt signaling pathway and the tumor microenvironment.
References from our work:
1, Kalra et al. PLoS Biology, 2012. 2, Keerthikumar et al. Oncotarget, 2015. 3, Cossetti et al. Molecular Cell, 2014. 4, Chisanga et al. Nucleic Acids Research, 2016 (In press)