Modeling Wnt signaling by CRISPR-Cas9 genome editing recapitulates neoplasia in human Barrett epithelial organoids

Cancer Letters
Xi LiuStephen J Meltzer

Abstract

Primary organoid cultures generated from patient biopsies comprise a novel improved platform for disease modeling, being genetically stable and closely recapitulating in vivo scenarios. Barrett esophagus (BE) is the major risk factor for esophageal adenocarcinoma. There has been a dearth of long-term in vitro expansion models of BE neoplastic transformation. We generated a long-term virus-free organoid expansion model of BE neoplasia from patient biopsies. Both wild-type and paired APC-knockout (APCKO) BE organoids genome-edited by CRISPR-Cas9 showed characteristic goblet cell differentiation. Autonomous Wnt activation was confirmed in APCKO organoids by overexpression of Wnt target genes and nuclear-translocated β-catenin expression after withdrawal of Wnt-3A and R-spondin-1. Wnt-activated organoids demonstrated histologic atypia, higher proliferative and replicative activity, reduced apoptosis, and prolonged culturability. Wnt-activated organoids also showed sustained protrusive migration ability accompanied by disrupted basement membrane reorganization and integrity. This CRISPR-Cas9 editing human-derived organoid model recapitulates the critical role of aberrant Wnt/β-catenin signaling activation in BE neoplastic transforma...Continue Reading

References

Apr 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·R F BoyntonS J Meltzer
Apr 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·P L BlountB J Reid
Jan 6, 1999·Proceedings of the National Academy of Sciences of the United States of America·M AokiP K Vogt
Apr 14, 1999·Cell Death and Differentiation·A G Porter, R U Jänicke
Oct 26, 2000·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Y W ChoiT T Wu
Nov 18, 2000·Journal of the National Cancer Institute·K KawakamiS J Meltzer
Feb 15, 2007·Expert Opinion on Therapeutic Targets·Geneviève ClémentJean Benhattar
May 19, 2007·Diseases of the Esophagus : Official Journal of the International Society for Diseases of the Esophagus·M K SchmidtR R Gurski
Jun 24, 2009·Nature Reviews. Molecular Cell Biology·Peter Friedl, Darren Gilmour
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
May 24, 2012·The EMBO Journal·Jurian Schuijers, Hans Clevers
Jun 2, 2012·The Journal of Pathology·Lisa H MoyesPeter D Adams
Aug 28, 2012·Proceedings of the National Academy of Sciences of the United States of America·Kim-Vy Nguyen-NgocAndrew J Ewald
Dec 22, 2012·Nature Reviews. Cancer·Jamie N Anastas, Randall T Moon
Aug 28, 2014·The New England Journal of Medicine·Stuart J Spechler, Rhonda F Souza
Sep 24, 2014·Methods in Molecular Biology·Kim-Vy Nguyen-NgocAndrew J Ewald
Apr 30, 2015·Nature·Jarno DrostHans Clevers
May 6, 2015·Seminars in Cancer Biology·Ramzi M MohammadAsfar S Azmi
Jul 21, 2015·Nature Genetics·Matthew D StachlerAdam J Bass
Aug 25, 2015·Neoplasia : an International Journal for Oncology Research·Orestis LyrosReza Shaker
Nov 4, 2015·The American Journal of Gastroenterology·Nicholas J ShaheenUNKNOWN American College of Gastroenterology
Feb 26, 2016·Annual Review of Pathology·James T Neal, Calvin J Kuo
Feb 26, 2016·Nature Cell Biology·Aliya FatehullahNick Barker
Jun 18, 2016·Cell·Hans Clevers
Mar 28, 2017·Trends in Molecular Medicine·Devanjali DuttaHans Clevers
Apr 27, 2017·The Journal of Cell Biology·Pamela RiemerMarkus Morkel

❮ Previous
Next ❯

Citations

Jun 7, 2019·Science·David Tuveson, Hans Clevers
Feb 27, 2020·Nature Reviews. Gastroenterology & Hepatology·Harry Cheuk Hay LauJun Yu
Mar 19, 2020·Journal of Gastroenterology and Hepatology·Biran PanJing Shan
Jul 31, 2020·British Journal of Cancer·Ross J PorterMairi H McLean
Jul 12, 2020·Journal of Molecular Cell Biology·Ramon U Jin, Jason C Mills
Jan 21, 2021·Experimental Biology and Medicine·Lin WangYoon-Young Jang
Jun 19, 2021·Nature Cancer·Yuan-Hung LoCalvin J Kuo
Sep 22, 2021·Journal of Molecular Biology·Shalaka PatilKundan Sengupta

❮ Previous
Next ❯

Related Concepts

Related Feeds

CRISPR Ribonucleases Deactivation

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on mechanisms that underlie deactivation of CRISPR ribonucleases. Here is the latest research.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Basement Membranes

Basement membranes are thin, specialized extracellular matrices surrounding most tissues in all metazoans. Here is the latest research on basement membranes.

Adherens Junctions

An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques). Adherens junctions uniquely disassemble in uterine epithelial cells to allow the blastocyst to penetrate between epithelial cells. Discover the latest research on adherens junctions here.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.

CRISPR (general)

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). CRISPR-Cas system enables the editing of genes to create or correct mutations. Discover the latest research on CRISPR here.

Virology & CRISPR

This feed focuses on the virology of CRISPR and its use in developing CRISPR-Cas systems. Discover the latest research here.

CRISPR for Genome Editing

Genome editing technologies enable the editing of genes to create or correct mutations. Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). Here is the latest research on the use of CRISPR-Cas system in gene editing.

Cadherins and Catenins

Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells: alpha-catenin can bind to β-catenin and can also bind actin. β-catenin binds the cytoplasmic domain of some cadherins. Discover the latest research on cadherins and catenins here.

CRISPR in Cancer

CRISPR-Cas system enables the editing of genes to create or correct mutations. Given that genome instability and mutation is one of the hallmarks of cancer, the CRISPR-Cas system is being explored to genetically alter and eliminate cancer cells. Here is the latest research.

Barrett Esophagus

Barrett’s esophagus if a serious complication of gastroesophageal reflux disease during which the normal esophageal lining changes to tissue that resembles intestinal lining. Here is the latest research.