title: Tripartite interactions between Wnt signaling, Notch and Myb for stem/progenitor cell functions during intestinal tumorigenesis.
abstract: Deletion studies confirm Wnt, Notch and Myb transcriptional pathway engagement in intestinal tumorigenesis. Nevertheless, their contrasting and combined roles when activated have not been elucidated. This is important as these pathways are not ablated but rather are aberrantly activated during carcinogenesis. Using ApcMin/+ mice as a source of organoids we documented their transition, on a clone-by-clone basis, to cyst-like spheres with constitutively activated Wnt pathway, increased self-renewal and growth and reduced differentiation. We then looked at this transition when Myb and/or Notch1 are activated. Activated Notch promoted cyst-like organoids. Conversely growth and propagation of cyst-like, but not normal organoids were Notch-independent. Activated Myb promoted normal, but not cyst-like organoids. Interestingly the Wnt, Notch and Myb pathways were all involved in regulating the expression of the intestinal stem cell (ISC) gene Lgr5 in organoids, while ISC gene and Notch target Olfm4 was dominantly repressed by Wnt. These findings parallel mouse intestinal adenoma formation where Notch promoted the initiation, but not growth, of Wnt-driven Olfm4-repressed colon tumors. Also Myb was essential for colon tumor initiation and collateral mouse pathologies. These data reveal the complex interplay and hierarchy of transcriptional networks that operate in ISCs and uncover a shift in pathway-dependencies during tumor initiation.
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Markus
authors.initials: M
authors.lastname: Germann
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Cancer Department of Oncology, University of Melbourne, Australia; Department of Pathology, The University of Melbourne, Australia.
authors.forename: Huiling
authors.initials: H
authors.lastname: Xu
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Cancer Department of Oncology, University of Melbourne, Australia.
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Cancer Department of Oncology, University of Melbourne, Australia.
authors.forename: Shienny
authors.initials: S
authors.lastname: Sampurno
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75248, Cedex 05, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Huyghe
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Cancer Department of Oncology, University of Melbourne, Australia.
authors.forename: Dane
authors.initials: D
authors.lastname: Cheasley
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75248, Cedex 05, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fre
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Cancer Department of Oncology, University of Melbourne, Australia; Department of Pathology, The University of Melbourne, Australia. Electronic address: rob.ramsay@petermac.org.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009940:Organoids / Q000166:cytology / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: C493597:Lgr5 protein, mouse; D009419:Nerve Tissue Proteins; D020598:Proto-Oncogene Proteins c-myb; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; D051153:Wnt Proteins