Different in vivo and in vitro transformation of intestinal stem cells in mismatch repair deficiency

Keysselt, K; Kreutzmann, Tobias; Rother, Karen; Kerner, Christiane; Krohn, Knuth; Przybilla, Jens; Buske, Peter; Löffler-Wirth, Henry; Loeffler, Markus; Galle, Joerg; Aust, Gabriela

doi:10.1038/onc.2016.429

Cited by 14 publications

(28 citation statements)

References 41 publications

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“…We first evaluated MSI in skin tumors from K14ΔNLef1 mice and K14ΔNLef1:cKO mice. We analyzed the relative allele frequency of five microsatellite regions, as previously described (Woerner et al , ; Germano et al , ; Keysselt et al , ). Three markers (Bat64, AA003063, and L24372) showed a shift in allele distribution, two of which were significant (Fig C).…”

Section: Resultsmentioning

confidence: 99%

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Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

et al. 2019

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Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β‐catenin‐independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9‐positive Lef1‐negative hair follicle progenitors that give rise to the upper SG. Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.

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Section: Resultsmentioning

confidence: 99%

“…PCR fragments were separated using Applied Biosystems Big‐Dye Ver 3.1 chemistry on an Applied Biosystems model 3730 automated capillary DNA sequencer. Raw data were visualized with Geneious software and further analyzed as previously described (Keysselt et al , ).…”

Section: Methodsmentioning

confidence: 99%

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

et al. 2019

View full text Add to dashboard Cite

show abstract

“…We first evaluated MSI in skin tumors from K14DNLef1 mice and K14DNLef1:cKO mice. We analyzed the relative allele frequency of five microsatellite regions, as previously described (Woerner et al, 2015;Germano et al, 2017;Keysselt et al, 2017). Three markers (Bat64, AA003063, and L24372) showed a shift in allele distribution, two of which were significant ( Fig 5C).…”

Section: Gata6 Acts As a Tumor Suppressor By Controlling The Dna Mismmentioning

confidence: 99%

“…PCR fragments were separated using Applied Biosystems Big-Dye Ver 3.1 chemistry on an Applied Biosystems model 3730 automated capillary DNA sequencer. Raw data were visualized with Geneious software and further analyzed as previously described (Keysselt et al, 2017).…”

Section: Microsatellite Instability Analysismentioning

confidence: 99%

Intersections between Regulated Cell Death and Autophagy

Napoletano

Baron

Vandenabeele

et al. 2019

Trends in Cell Biology

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Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a b-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG. Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.

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“…Notably, we report the novel observation that aspirin rescues the characteristic aberrant Wnt-driven cystic phenotype by promoting budding in human colonic organoids from patients with FAP. This intestinal organoid phenotype transition has only been observed previously in a mismatch repair deficient mouse model (Keysselt et al, 2017). Increased stem cell, specifically Lgr5, and mesenchymal marker expression is associated with poor survival in CRC (Xu et al, 2018) , .…”

Section: Discussionmentioning

confidence: 71%

Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

Dunbar

Valančiūtė

Rajasekaran

et al. 2019

Preprint

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Aspirin reduces the incidence and mortality of colorectal cancer (CRC). Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we investigated whether aspirin can rescue these pro-invasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids. Aspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in Apc Min/+ mice is associated with EMT inhibition and decreased cell migration, invasion and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 (DKK-1) in CRC cells and organoids derived from FAP patients. We provide evidence of phenotypic biomarkers of aspirin response with an increased epithelial and reduced stem-like state mediated by an increase in DKK-1. Thus we highlight a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.

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Different in vivo and in vitro transformation of intestinal stem cells in mismatch repair deficiency

Cited by 14 publications

References 41 publications

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

Intersections between Regulated Cell Death and Autophagy

Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

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