Rapid interrogation of cancer cell of origin through CRISPR editing

Weiran Feng, Zhen Cao, Pei Xin Lim, Huiyong Zhao, Hanzhi Luo, Ninghui Mao, Young Sun Lee, Aura Agudelo Rivera, Danielle Choi, Chao Wu, Teng Han, Rodrigo Romero, Elisa de Stanchina, Brett S Carver, Qiao Wang, Maria Jasin, Charles L Sawyers

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.

Original languageEnglish
Article numbere2110344118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number32
DOIs
StatePublished - Aug 5 2021
Externally publishedYes

Keywords

  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • CRISPR-Associated Protein 9/genetics
  • Chromosome Deletion
  • Clustered Regularly Interspaced Short Palindromic Repeats/genetics
  • Epithelial Cells
  • Gene Editing/methods
  • Genes, Tumor Suppressor
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Organoids
  • Prostate/cytology
  • Prostatic Neoplasms/genetics
  • RNA, Guide, CRISPR-Cas Systems
  • Ribonucleoproteins/genetics
  • Transcriptional Regulator ERG/genetics
  • Xenograft Model Antitumor Assays
  • Mice

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