Wnt Ligands Secreted by Subepithelial Mesenchymal Cells Are Essential for the Survival of Intestinal Stem Cells and Gut Homeostasis

Michel Aguet, Andreas Eduard Moor
Elsevier, 2016
Article

Résumé

Targeting of Wnt signaling represents a promising anti-cancer therapy. However, the consequences of systemically attenuating the Wnt pathway in an adult organism are unknown. Here, we globally prevent Wnt secretion by genetically ablating Wntless. We find that preventing Wnt signaling in the entire body causes mortality due to impaired intestinal homeostasis. This is caused by the loss of intestinal stem cells. Reconstitution of Wnt/beta-catenin signaling via delivery of external Wnt ligands prolongs the survival of intestinal stem cells and reveals the essential role of extra-epithelial Wnt ligands for the renewal of the intestinal epithelium. Wnt2b is a key extra-epithelial Wnt ligand capable of promoting Wnt/beta-catenin signaling and intestinal homeostasis. Wnt2b is secreted by subepithelial mesenchymal cells that co-express either Gli1 or Acta2. Subepithelial mesenchymal cells expressing high levels of Wnt2b are predominantly Gli1 positive.

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Canonical Wnt signaling plays a critical role in stem cell maintenance in epithelial homeostasis and carcinogenesis. Here, we show that in the mouse this role is critically mediated by Bcl9/Bcl9l, the mammalian homologues of Legless, which in Drosophila is required for Armadillo/beta-catenin signaling. Conditional ablation of Bcl9/Bcl9l in the intestinal epithelium, where the essential role of Wnt signaling in epithelial homeostasis and stem cell maintenance is well documented, resulted in decreased expression of intestinal stem cell markers and impaired regeneration of ulcerated colon epithelium. Adenocarcinomas with aberrant Wnt signaling arose with similar incidence in wild-type and mutant mice. However, transcriptional profiles were vastly different: Whereas wild-type tumors displayed characteristics of epithelial-mesenchymal transition (EMT) and stem cell-like properties, these properties were largely abrogated in mutant tumors. These findings reveal an essential role for Bcl9/Bcl9l in regulating a subset of Wnt target genes involved in controlling EMT and stem cell-related features and suggest that targeting the Bcl9/Bcl9l arm of Wnt signaling in Wnt-activated cancers might attenuate these traits, which are associated with tumor invasion, metastasis, and resistance to therapy.

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BCL9/9L proteins enhance the transcriptional output of the beta-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistentwith the notion that high WNT signaling is required for stemnessmaintenance, ablating Bcl9/9l-beta-catenin inmurine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targetingWNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome. (C) 2015 The Authors. Published by Elsevier B.V.

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The mammalian intestine is a prototype of a self-renewing organ. The rapid cellular turnover is supported by proliferating progenitors located in the intestinal crypt, which is also the stem cell location. Homeostasis of the intestinal epithelium has to be under stringent control to ensure lifelong self-renewal. Processes like proliferation and differentiation (often deregulated in cancer) seem to be controlled by a relative small number of signaling pathways, including Wnt and Notch. Notch signaling is playing a crucial role in the maintenance of the intestinal homeostasis by controlling progenitors proliferation and their cell fate. In this thesis project we studied Notch signaling and its role in the murine intestine focusing on 1) Its downstream mediators; 2) The identification of the physiological Notch ligands; 3) Its role on the stem cell compartment, and 4) the potential cross talk between Notch and Wnt. Furthermore, 5) we investigated the role of Notch signaling in Wnt induced intestinal tumorigenesis. This study evidenced that Hes1 is not the unique Notch signaling mediator in the intestinal epithelium. Moreover the transcription factor Klf4 is not required for goblet cell differentiation. The in vivo role of the Notch ligands Dll1, Dll4 and Jag1 was assessed deriving inducible intestine specific single and double gene-targeted mice. Inactivation of individual ligands did not show any loss of Notch phenotype with the exception of Dll1 mutant mice. Only by deriving double mutants we identified Dll1 and Dll4 as the physiological Notch ligands in the intestine. We provided evidence for the first time that Notch1 signaling is active in intestinal stem cell. Furthermore we demonstrated that Notch signaling is required for the maintenance of intestinal stem cells, as well as for the transit-amplifying progenitor compartment. Using different genetic gain and loss-off function approaches we investigated the relation between the Notch and Wnt cascade for the maintenance of the proliferative crypt compartment. A synergistic relation was observed between Notch and Wnt in intestinal tumorigenesis. Collectively our data highlight Notch signaling as a key player for the maintenance of intestinal homeostasis.

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