Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer.
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.
Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Alex
A
Gregorieff
Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, Ontario M5S 1A8, Canada.
Yu
Y
Liu
Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Mohammad R
MR
Inanlou
Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Yuliya
Y
Khomchuk
Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, Ontario M5S 1A8, Canada.
Jeffrey L
JL
Wrana
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D066260:Epiregulin / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000090683:Hippo Signaling Pathway; D006706:Homeostasis / Q000528:radiation effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology* / Q000528:radiation effects; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009940:Organoids / Q000378:metabolism; D019879:Paneth Cells / Q000166:cytology / Q000528:radiation effects; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011839:Radiation, Ionizing; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012038:Regeneration / Q000528:radiation effects; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D060449:Wnt Signaling Pathway; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D066260:Epiregulin; C587881:Ereg protein, mouse; C493597:Lgr5 protein, mouse; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases