Abstract 5397: ExomiRs can distinguish tumor-associated from normal stroma: Potential biomarkers in colorectal cancer

Abstract

Abstract There is urgent need for prognostic markers to stratify intermediate-stage colorectal cancer (CRC) patients for the benefit of adjuvant therapy. Tumor heterogeneity is a major obstacle in stratification attempts as rare cancer cell populations may display stem cell properties and allow generation of therapy resistance. Tumor stroma, on the other hand, is less susceptible to genetic alterations than cancer cells, providing signals that are more reproducible across patient samples. Exosome encapsulated microRNAs (exomiRs) are particularly amenable to biomarker development because they circulate, closely resemble the tissue of origin and are inherently stable. We sought to identify a stromal exomiR signature in colorectal cancer with biomarker potential. Paired primary tumor-associated and normal fibroblasts were extracted from human colonic tissue. Exosomes were isolated by differential ultracentrifugation, validated according to International Society for Extracellular Vesicles recommendations, and profiled for over 800 microRNAs (miRNAs) by NanoString. Data preprocessing and normalization was conducted prior to differential expression analysis. Candidate miRNAs were validated by qPCR. Pathway and network analyses were conducted using miRPath and Ingenuity Pathway Analysis. Forty one exomiRs were differentially present in tumor-associated and normal fibroblasts. Of these, 21 were more abundant in tumor-associated fibroblasts. Thirty-six KEGG pathways were found to be regulated by this exomiR signature, such as “PI3K-Akt” and “colorectal cancer.” A potential target of these exomiRs is PHLPP2, which encodes a phosphatase acting on AKT. In keeping with this, exposure to fibroblast exosomes increased AKT phosphorylation and that of its direct target Bad, in CRC cells, potentially due to a decrease in PHLPP2 protein abundance. Consequently, these cells were protected from drug-induced apoptosis. For the first time, stromal exomiRs have been profiled in colorectal cancer. Tumor-associated and normal stroma can be distinguished by a specific exomiR signature, which is potentially functionally important. Further mechanistic characterization is now required to identify the clinical significance of stromal exomiRs. Citation Format: Rahul Bhome, Rebecca Goh, Nir Pillar, Noam Shomron, Emre Sayan, Alex Mirnezami. ExomiRs can distinguish tumor-associated from normal stroma: Potential biomarkers in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5397.