Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells

PloS One
Cesar A SommerGustavo Mostoslavsky

Abstract

Mutations in the gene Adenomatous Polyposis Coli or APC appear in most sporadic cases of colorectal cancer and it is the most frequent mutation causing hereditary Familial Adenomatous Polyposis. The detailed molecular mechanism by which APC mutations predispose to the development of colorectal cancer is not completely understood. This is in part due to the lack of accessibility to appropriate models that recapitulate the early events associated with APC mediated intestinal transformation. We have established a novel platform utilizing human induced Pluripotent Stem cells or iPSC from normal or FAP-specific APC mutant individuals and evaluated the effect of the mutation in the cells before and after differentiation into intestinal organoids. In order to minimize genetic background effects, we also established an isogenic platform using TALEN-mediated gene editing. Comparison of normal and APC mutant iPSC revealed a significant defect in cell identity and polarity due to the presence of APC in heterozygosity as well as chromosomal aberrations including abnormal anaphases and centrosome numbers. Importantly, upon specification into intestinal progeny, APC heterozygosity was responsible for a major change in the transcriptional ide...Continue Reading

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Citations

Jul 6, 2019·Médecine sciences : M/S·Charlotte FlatresMaxime M Mahé
Jan 12, 2020·Nature Communications·Aditya MithalGustavo Mostoslavsky
Aug 29, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Tristan Frum, Jason R Spence
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Jul 12, 2020·Journal of Molecular Cell Biology·Fong Cheng PanShuibing Chen
Mar 2, 2019·Reports of Practical Oncology and Radiotherapy : Journal of Greatpoland Cancer Center in Poznań and Polish Society of Radiation Oncology·Patrycja CzerwińskaMaciej Wiznerowicz
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Datasets Mentioned

BETA
GM03954
GM06888
GM06965

Methods Mentioned

BETA
ubiquitination
transfection
PCR
flow cytometry
Assay
chromosomal aberrations
RNA seq
chip

Software Mentioned

Gene Set Enrichment Analysis ( GSEA )
STEMCCA
R
Bioconductor
TAL Effector Nucleotide Targeter
Ingenuity® Pathway Analysis ( IPA )
IPA
Gen Set Enrichment Analysis
GSEA
Ingenuity Pathway Analysis ( IPA )

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