Loss of Rab11 synergizes with oncogenic Ras to alter growth and metabolism in intestinal cancer models

Cancer in the intestinal tract is governed by multiple pathways including Wnt, Ras, P53 and Hippo. The GTPase Rab11 regulates endosomal protein trafficking and in a previous report we showed that loss of Rab11 in enterocytes caused intestinal inflammation and hyperplasia in mice and flies. We show here that this inflammation may cooperate with cancer promoting pathways in the intestinal tract. First, lower Rab11 protein staining was observed in 63 out of 70 human colon cancer tissues and patients of age older than 70 had particularly consistent lower Rab11 level. Second, tissue specific knockout of Rab11a in the mouse intestinal epithelium enhanced the formation of intestinal adenocarcinoma after AOM feeding. Third, by using the Drosophila midgut as an experiment model, we show that loss of Rab11 synergizes with the oncoprotein RasV12 to promote cancer-related phenotypes. Fourth, the target genes of this synergistic interaction include the JAK-STAT pathway ligand Upd3 and the IGF pathway antagonist ImpL2. The expression of Upd3 promotes intestinal stem cell proliferation, while ImpL2 suppresses the metabolism of surrounding tissues. Our results demonstrate that a reduced Rab11 function may contribute to intestinal cancer progression by enhancing the growth and metabolic defects initiated by other tumor promoting pathways. Overall design: Differential gene expression analysis from Drosophila melanogaster midgut mRNA profiling of wild type control flies and Rab11 RNAi flies driven by Myo1AGal4, using Illumina and Ion Torrent