C. elegans DAF-16/FOXO interacts with TGF-ß/BMP signaling to induce germline tumor formation via mTORC1 activation

Activation of the foxo transcription factor daf-16 by reduced insulin/igf signaling (iis) is considered to be beneficial in c. elegans due to its ability to extend lifespan and to enhance stress resistance. in the germline,cell-autonomous daf-16 activity prevents stem cell proliferation,thus acting tumor-suppressive. in contrast,hypodermal daf-16 causes a tumorous germline phenotype characterized by hyperproliferation of the germline stem cells and rupture of the adjacent basement membrane. here we show that cross-talk between daf-16 and the transforming growth factor ß (tgfß)/bone morphogenic protein (bmp) signaling pathway causes germline hyperplasia and results in disruption of the basement membrane. in addition to activating madm/nrbp/hpo-11 genes alone,daf-16 also directly interacts with both r-smad proteins sma-2 and sma-3 in the nucleus to regulate the expression of mtorc1 pathway. knocking-down of bmp genes or each of the four target genes in the hypodermis was sufficient to inhibit germline proliferation,indicating a cell-non-autonomously controlled regulation of stem cell proliferation by somatic tissues. we propose the existence of two antagonistic daf-16/foxo functions,a cell-proliferative somatic and an anti-proliferative germline activity. whereas germline hyperplasia under reduced iis is inhibited by daf-16 cell-autonomously,activation of somatic daf-16 in the presence of active iis promotes germline proliferation and eventually induces tumor-like germline growth. in summary,our results suggest a novel pathway crosstalk of daf-16 and tgf-ß/bmp that can modulate mtorc1 at the transcriptional level to cause stem-cell hyperproliferation. such cell-type specific differences may help explaining why human foxo activity is considered to be tumor-suppressive in most contexts,but may become oncogenic,e.g. in chronic and acute myeloid leukemia. © 2017 qi et al.