Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer

Abstract

The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling in Lgr5(+) intestinal stem cells (ISCs). However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration. Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing radiation. Yap transiently reprograms Lgr5(+) ISCs by suppressing Wnt signalling and excessive Paneth cell differentiation, while promoting cell survival and inducing a regenerative program that includes Egf pathway activation. Accordingly, growth of Yap-deficient organoids is rescued by the Egfr ligand epiregulin, and we find that non-cell-autonomous production of stromal epiregulin may compensate for Yap loss in vivo. Consistent with key roles for regenerative signalling in tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in the Apc(Min) mouse model of colon cancer, and that Yap-driven expansion of Apc(-/-) organoids requires the Egfr module of the Yap regenerative program. Finally, we show that in vivo Yap is required for progression of early Apc mutant tumour-initiating cells, suppresses their differentiation into Paneth cells, and induces a regenerative program and Egfr signalling. Our studies reveal that upon tissue injury, Yap reprograms Lgr5(+) ISCs by inhibiting the Wnt homeostatic program, while inducing a regenerative program that includes activation of Egfr signalling. Moreover, our findings reveal a key role for the Yap regenerative pathway in driving cancer initiation.

Pituitary stem cell regulation: who is pulling the strings?

“…The Hippo pathway may thus be implicated in the regenerative response of the pituitary stem cells, in agreement with its involvement in (stem cell-driven) repair in other tissues like the intestine (Gregorieff et al 2015) and heart (Heallen et al 2013, Xin et al 2013.…”

“…repressing YAP/TAZ) may thus exert tumor-suppressive activity. The Hippo system may also interact with WNT signaling since Yap1 deletion blocked the development of adenomas in WNT-activated Apc −/− intestinal crypts (Gregorieff et al 2015). Implication of Hippo in pituitary tumorigenesis is still uncharted although enrichment of various Hippo pathway components (e.g.…”

“…Genetically enhanced YAP/TAZ activity in the adult heart stimulates cardiac regeneration after myocardial infarction (Heallen et al 2013, Xin et al 2013. In the intestine, YAP was found indispensable for regeneration of the epithelium by the intestinal stem cells after irradiation (Gregorieff et al 2015).…”

Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

“…These results suggest that SFKs negatively regulate Wnt-␤-catenin signaling. Given that YAP is thought to inhibit the Wnt-␤-catenin signaling pathway (48)(49)(50), SFKs likely target this pathway through upregulation of YAP activity in crypt IECs. We also found that IEC-specific ablation of Csk increased the number of goblet cells in the ileum as well as in intestinal organoids and that expression of the Notch target genes Olfm4 and Hes1 (9, 51) was downregulated in crypts of Csk CKO mice ( Fig.…”

R-spondin 2 promotes proliferation and migration via the Wnt/β-catenin pathway in human hepatocellular carcinoma

“…It was demonstrated that RSPOs cooperate with Wnts during development, particularly by promoting the transcriptional activity of β-catenin, which is an important mechanism of the Wnt signaling pathway (5,16). It has been revealed that canonical Wnt/β-catenin signaling serves an important role in numerous cancer types, including lung, breast, brain, colorectal and liver tumors (21)(22)(23). Interaction between RSPOs and LGR4, as well as the intracellular signaling proteins, promotes phosphorylation of LRP5/6, stabilizes β-catenin expression and promotes its transcriptional activity (18).…”