We recently found that re-routing intracellular vesicle traffic by suppressing macroautophagy/autophagy or endocytosis genes drastically deregulates Drosophila intestinal stem cell (ISC) proliferation, leading to massive gut hyperplasia that has a negative impact upon lifespan. Beginning with the poorly characterized Snx (sorting nexin) genes, we surveyed a broad set of genes in the endocytosis-autophagy network and found that most of them have this effect. We then discovered that deregulated Egfr-Ras85D/Ras1-mitogen-activated protein kinase signaling is the primary trigger for ISC proliferation upon disruption of this network and determined that in the mutants, ligand-activated receptors were stabilized and recycled to the cell surface via Rab11-dependent endosomes, rather than being degraded via autophagosomes. We profiled the mutational landscape for orthologous network genes in human cancers using The Cancer Genome Atlas (TCGA), and revealed strong, novel associations with distinct genomic and epigenomic subtypes of colorectal cancer.
Keywords: Drosophila; Egfr-Ras-MAPK signaling; colorectal cancer; endocytosis-autophagy network; intestinal stem cell (ISC) proliferation; sorting nexins (SNXs).