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 gene 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.

因胰岛素/胰岛素样生长因子信号（IIS）下调而激活的叉头框O（FOXO）转录因子DAF-16，在秀丽隐杆线虫（C. elegans）中被认为具有有益效应，因其可延长寿命并增强应激抵抗能力。在生殖系中，细胞自主性DAF-16活性可抑制干细胞增殖，从而发挥肿瘤抑制作用。与之相反，皮下组织中的DAF-16则会引发生殖系肿瘤表型，其特征为生殖系干细胞过度增殖以及邻近基底膜破裂。本研究证实，DAF-16与转化生长因子β（TGF-β）/骨形态发生蛋白（BMP）信号通路之间的串扰可导致生殖系增生，并引发基底膜破坏。除单独激活MADM/NRBP/hpo-11基因外，DAF-16还可在细胞核内直接与R-SMAD蛋白SMA-2及SMA-3相互作用，以调控雷帕霉素靶蛋白复合物1（mTORC1）通路的基因表达。在皮下组织中敲低BMP基因或四个靶基因中的任意一个，即可有效抑制生殖系增殖，这表明体细胞组织可通过细胞非自主性方式调控干细胞增殖。我们提出存在两种相互拮抗的DAF-16/FOXO功能：一种是促进体细胞增殖的功能，另一种是抑制生殖系增殖的功能。在IIS下调的情况下，生殖系增生可被细胞自主性的DAF-16所抑制；而在IIS激活的状态下，体细胞DAF-16的激活则会促进生殖系增殖，并最终诱发肿瘤样生殖系生长。综上，本研究结果揭示了DAF-16与TGF-β/BMP之间一种全新的通路串扰机制：该机制可在转录水平调控mTORC1，进而导致干细胞过度增殖。这种细胞类型特异性的功能差异，或可解释为何在多数情境下人类FOXO活性被认为具有肿瘤抑制作用，但在某些情况下（如慢性髓系白血病与急性髓系白血病）却可能成为致癌因素。