title: Different in vivo and in vitro transformation of intestinal stem cells in mismatch repair deficiency.
abstract: Mutations in mismatch repair (MMR) genes result in microsatellite instability (MSI) and early onset of colorectal cancer. To get mechanistic insights into the time scale, sequence and frequency of intestinal stem cell (ISC) transformation, we quantified MSI and growth characteristics of organoids of Msh2-deficient and control mice from birth until tumor formation and related them to tissue gene expression. Although in Msh2-deficient organoids MSI continuously increased from birth, growth characteristics remained stable at first. Months before tumor onset, normal Msh2-deficient tissue contained tumor precursor cells forming organoids with higher MSI, cystic growth and growth rates resembling temporarily those of tumor organoids. Consistently, Msh2-deficient tissue exhibited a tumor-like gene signature. Normal Msh2-deficient organoids showed increased inheritable transient cyst-like growth, which became independent of R-spondin. ISC transformation proceeded faster in vitro than in vivo independent of the underlying genotype but more under MMR deficiency. Transient cyst-like growth but not MSI was suppressed by aspirin. In summary, as highlighted by organoids, molecular alterations continuously proceeded long before tumor onset in MMR-deficient intestine, thus increasing its susceptibility for ISC transformation.
authors.affiliation: Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Keysselt
authors.affiliation: Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Kreutzmann
authors.affiliation: Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany.|Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Leipzig, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Rother
authors.affiliation: Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kerner
authors.affiliation: Interdisciplinary Center for Clinical Research Leipzig (IZKF), Core-Unit DNA Technologies, University of Leipzig, Leipzig, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Leipzig, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Przybilla
authors.affiliation: Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Leipzig, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Buske
authors.affiliation: Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Leipzig, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Löffler-Wirth
authors.affiliation: Institute for Medical Statistics, Informatics and Epidemiology, University of Leipzig, Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Loeffler
authors.affiliation: Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Leipzig, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Galle
authors.affiliation: Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Aust
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007422:Intestines / Q000254:growth & development / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053842:Microsatellite Instability; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology
chemical_list: C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein