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
• colorectal cancer
• Egfr-Ras-MAPK signaling
• endocytosis-autophagy network
• intestinal stem cell (ISC) proliferation
• sorting nexins (SNXs)

Acknowledgments

This work was supported by the Huntsman Cancer Foundation and the Center for Genomic Medicine/Utah Genome Project at the University of Utah (to B.A.E. and C.M.U.) and grants from the National Institutes of Health (NIH: R01 GM124434 to B.A.E.; P30 CA042014 to B.A.E. and C.M.U.; U01 CA206110, R01 CA189184, and R01 CA211705 to C.M.U.). A.N.H. was supported by the National Human Genome Research Institute (T32 HG008962).

Disclosure statement

The authors declare no conflict of interest with this work. C.M.U. has as cancer center director oversight over research funded by several pharmaceutical companies but has not received funding directly herself.

Additional information

Funding

This work was supported by the National Institutes of Health [R01 GM124434]; National Institutes of Health [P30 CA042014]; National Institutes of Health [P30 CA042014]; National Institutes of Health [U01 CA206110]; National Institutes of Health [R01 CA189184]; National Institutes of Health [R01 CA211705]; National Human Genome Research Institute [T32 HG008962].