Integrated genome and tissue engineering enables screening of cancer vulnerabilities in physiologically relevant perfusable ex vivo cultures.
Bioprinting
Breast cancer model
CRISPR screens
Medulloblastoma model
Point-of-care functional screens
Journal
Biomaterials
ISSN: 1878-5905
Titre abrégé: Biomaterials
Pays: Netherlands
ID NLM: 8100316
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
25
09
2021
revised:
10
11
2021
accepted:
23
11
2021
pubmed:
11
12
2021
medline:
15
3
2022
entrez:
10
12
2021
Statut:
ppublish
Résumé
Genetic screens are powerful tools for both resolving biological function and identifying potential therapeutic targets, but require physiologically accurate systems to glean biologically useful information. Here, we enable genetic screens in physiologically relevant ex vivo cancer tissue models by integrating CRISPR-Cas-based genome engineering and biofabrication technologies. We first present a novel method for generating perfusable tissue constructs, and validate its functionality by using it to generate three-dimensional perfusable dense cultures of cancer cell lines and sustain otherwise ex vivo unculturable patient-derived xenografts. Using this system we enable large-scale CRISPR screens in perfused tissue cultures, as well as emulate a novel point-of-care diagnostics scenario of a clinically actionable CRISPR knockout (CRISPRko) screen of genes with FDA-approved drug treatments in ex vivo PDX cell cultures. Our results reveal differences across in vitro and in vivo cancer model systems, and highlight the utility of programmable tissue engineered models for screening therapeutically relevant cancer vulnerabilities.
Identifiants
pubmed: 34890975
pii: S0142-9612(21)00633-5
doi: 10.1016/j.biomaterials.2021.121276
pmc: PMC9328412
mid: NIHMS1822088
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
121276Subventions
Organisme : NCI NIH HHS
ID : R01 CA159859
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM123313
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222826
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009285
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA209891
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
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