One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids

Maarten H. Geurts (), Shashank Gandhi, Matteo G. Boretto, Ninouk Akkerman, Lucca L. M. Derks, Gijs Son, Martina Celotti, Sarina Harshuk-Shabso, Flavia Peci, Harry Begthel, Delilah Hendriks, Paul Schürmann, Amanda Andersson-Rolf, Susana M. Chuva de Sousa Lopes, Johan H. Es, Ruben Boxtel and Hans Clevers ()
Additional contact information
Maarten H. Geurts: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Shashank Gandhi: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Matteo G. Boretto: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Ninouk Akkerman: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Lucca L. M. Derks: Oncode Institute
Gijs Son: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Martina Celotti: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Sarina Harshuk-Shabso: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Flavia Peci: Oncode Institute
Harry Begthel: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Delilah Hendriks: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Paul Schürmann: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Amanda Andersson-Rolf: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Susana M. Chuva de Sousa Lopes: Leiden University Medical Center, Einthovenweg
Johan H. Es: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht
Ruben Boxtel: Oncode Institute
Hans Clevers: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Optimization of CRISPR/Cas9-mediated genome engineering has resulted in base editors that hold promise for mutation repair and disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived organoids. First we show efficacy of cytosine and adenine base editors in modeling CTNNB1 hot-spot mutations in hepatocyte organoids. Next, we use C > T base editors to insert nonsense mutations in PTEN in endometrial organoids and demonstrate tumorigenicity even in the heterozygous state. Moreover, drug sensitivity assays on organoids harboring either PTEN or PTEN and PIK3CA mutations reveal the mechanism underlying the initial stages of endometrial tumorigenesis. To further increase the scope of base editing we combine SpCas9 and SaCas9 for simultaneous C > T and A > G editing at individual target sites. Finally, we show that base editor multiplexing allow modeling of colorectal tumorigenesis in a single step by simultaneously transfecting sgRNAs targeting five cancer genes.

Date: 2023
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DOI: 10.1038/s41467-023-40701-3

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