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KRAS-dependent sorting of miRNA to exosomes

Cancer cells can undergo activating mutations in oncogenes or loss of function mutations in tumor suppressors that drive cancer progression. Many colorectal cancers have activating mutations in the small GTPase KRAS, which leads to more aggressive tumors. Such mutations can also prevent some cancers from responding to specific drug treatments. In our previous studies, we found that the contents of the exosomes released from these mutant KRAS colorectal cancer cells can influence cells with wild-type KRAS and promote oncogenesis in the tumor microenvironment (Beckler et al., 2013; Higginbotham et al., 2011). Furthermore, the exosomes released from KRAS mutant cells contain different proteins than those from cells with wild type KRAS. To test whether mutant KRAS might regulate the composition of secreted miRNAs that contributes to changes in gene expression in recipient cells, we compared small RNAs of cells and matched purified exosomes from isogenic CRC cell lines differing only in KRAS status. The results from this study were recently published in the journal elife (Cha et al., 2015).

We find that exosomes released by mutant KRAS cells contain miRNAs that are different from wild type KRAS cell-derived exosomes. In particular, several miRNAs that function to suppress cancer growth in a healthy cell are found at lower levels in mutant KRAS cells. One such miRNA is miR-100 and was highly represented in the exosomes that are released by KRAS mutant cells.

Reporter gene constructs that are targeted and downregulated by miRNAs were used to test for transfer of functional miRNA species between cells. When cells with a normal copy of the KRAS gene were exposed to the contents of the exosomes released from KRAS mutant cells, we found a reporter for the predicted miR-100 target mTOR was suppressed, indicating that the exported miRNAs from cancerous cells can influence gene expression in neighboring cells. Selective secretion of such cancer-suppressing miRNAs could give cancer cells with mutant KRAS an additional growth advantage over surrounding cells with wild type KRAS that retain such miRNAs. By monitoring the levels of circulating miRNAs in patients, it might be possible to create a non-invasive test to detect colorectal cancer and to influence potential efficacious treatments depending on a patient’s tumor mutational status.

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