Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis

Abstract

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).

Figures

Figure 1.

The role of autophagy in regulation of intestinal stem cell proliferation and colorectal cancer progression. Blockages in the autophagy pathway stabilize Egfr, which autonomously activates ISC proliferation. Excess ISC divisions trigger general epithelial stress, EC-localized yki and rho (Egfr ligand splicer) activation, which promote the production of upd3 and the activation of Egfr ligands, respectively. This catalyzes a feedforward reaction and massive ISC hyperplasia. ISC hyperproliferation-generated local mechano-stress could potentially magnify proliferation signals. This process mimics carcinogenic processes (from early-stage cancer stem cells to cancer), and suggests a tumor suppressive role for autophagy in early stages of colorectal cancer progression. ISC, intestinal stem cell; EB, enteroblast; EC, enterocyte; VM, visceral muscle; yki, yorkie; upd3, unpaired 3; rho, rhomboid.