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Non-cellautonomous role of the endoribonuclease ENDU-2/ENDOU/PP11 in tumorigenesis and invasion

Project Summary

Alterations in endocytosis/exocytosis are being increasingly recognized as a major contributor to tumorigenesis. We showed that imbalances in insulin/IGF signaling (IIs) in somatic tissues of C. elegans are sufficient to induce germline stem cell tumors in a non-cellautonomous manner (Qi et al., 2012, 2017). Somatic interactions of the IIs effector FOXO/DAF-16 with components of the BMP pathway were found to be responsible to activate expression of various downstream genes, including those of mTORC1 signaling. We identified a novel endoribonuclease, conserved also in the human genome, as being sufficient for germline tumor induction. Reduced expression of the respective gene in somatic tissues results in chromatin aberrations and germline stem cell mortality. Upon stress, endoribonuclease gene expression is further induced, and the protein is release from somatic tissues is a prerequisite for its function in stem cells, suggesting that a combined exo/endocytosis mechanism contributes to this non-cell-autonomous tumor induction. This suggest that a tight control of its activity is necessary to balance immortality and tumorigenesis. A combination of biochemical and genetic experiments in human cell culture and C. elegans is proposed to analyze the regulation, function, interactions and mechanistic targets of this stress induced factor.