Abstract 3083: Global gene expression profiling of mice tumor-derived organoids identifies key microRNAs and metabolic genes involved in CRC progression

Abstract

Abstract Background. Progressive accumulation of mutations in oncogenic and tumor suppressor pathways are associated with colorectal cancer (CRC). Mutations in APC, KRAS and p53 represent key drivers events in CRC initiation and progression and are simultaneously mutated in about 30% of CRC. Tumor derived Organoids (TDO) are three-dimensional (3-D) structures composed of cells that are spatially organized like mini-guts and represent a useful ex vivo tool to study intestinal physiology and cancer progression. Here, we investigated the progressive deregulation of mRNA and microRNA (miRNA) genes in TDOs from intestines of three different Genetically Engineered Mouse models (GEMMs) harboring mutations in Apc, Apc plus Kras and Apc plus Kras and p53. Methods. Array analysis of protein coding and non-coding RNAs from mice TDOs was performed to identify mRNAs and miRNAs that were differentially expressed following Apc, Kras and p53 mutations. Agilent Feature Extraction software was used to analyze acquired array images and subsequent data processing was performed by the GeneSpring GX v11.5.1 software package. Results. Twenty-five% of mRNAs showed more than 2 fold changes in expression level and considered differentially expressed. Pathway analysis found that a great number of mRNAs, which were significantly differentially expressed (P-value 0.001), were involved in metabolic process. Of these, 10 were involved in metabolism of different amino acids or other compounds (e.g., arachidonic acid, ascorbate, alendrate, and linoleic acid) and 4 were encoding the cytochrome p450 family drug and xenobiotic metabolizing enzymes. In addition, 28 and 10% of miRNAs in Apc vs Apc/Kras and Apc/Kras vs Apc/Kras/p53 respectively were identified as differentially expressed miRNA. Twenty-two of these miRNAs were related to deregulated metabolic genes in this study. Selected metabolic genes (e.g., Pipox) were constantly down regulated from early (Apc only mutants) to advanced (Apc/Kras/p53 mutants) CRC, whereas their associated miRNAs (mir-883a-3p and mir-1943) were constantly up regulated. High expression level of mir-125 which was detected in Apc/Kras/p53 group was also associated to down regulation of associated metabolic genes: Pipox and Ggt7. Conclusions. Using 3-D TDOs, we have identified deregulated miRNAs that are involved in regulation of metabolic pathways associated with CRC progression. Further analysis of miRNA-mRNA interaction in these models may help identify metabolic vulnerabilities that may be exploited for CRC therapy. Citation Format: Mahnaz Darvish Damavandi, Chiara Braconi, Luciano Cascione, Andrea Lampis, Jens Hahne, Claudio Murgia, Michele Ghidini, Gift Nyamundanda, Anguraj Sadanandam, Carlo Croce, Owen Sansom, Nicola Valeri. Global gene expression profiling of mice tumor-derived organoids identifies key microRNAs and metabolic genes involved in CRC progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3083. doi:10.1158/1538-7445.AM2015-3083