Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells.
KRAS
alveolar
developmental programs
early-stage lung cancer
iPSC
loss of differentiation
organoid
single-cell RNA sequencing
stage IA lung adenocarcinoma
tumor progression
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
26
05
2020
revised:
09
07
2020
accepted:
29
07
2020
pubmed:
7
9
2020
medline:
28
4
2021
entrez:
6
9
2020
Statut:
ppublish
Résumé
Mutant KRAS is a common driver in epithelial cancers. Nevertheless, molecular changes occurring early after activation of oncogenic KRAS in epithelial cells remain poorly understood. We compared transcriptional changes at single-cell resolution after KRAS activation in four sample sets. In addition to patient samples and genetically engineered mouse models, we developed organoid systems from primary mouse and human induced pluripotent stem cell-derived lung epithelial cells to model early-stage lung adenocarcinoma. In all four settings, alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS had reduced expression of mature lineage identity genes. These findings demonstrate the utility of our in vitro organoid approaches for uncovering the early consequences of oncogenic KRAS expression. This resource provides an extensive collection of datasets and describes organoid tools to study the transcriptional and proteomic changes that distinguish normal epithelial progenitor cells from early-stage lung cancer, facilitating the search for targets for KRAS-driven tumors.
Identifiants
pubmed: 32891189
pii: S1934-5909(20)30360-X
doi: 10.1016/j.stem.2020.07.022
pmc: PMC7541765
mid: NIHMS1619122
pii:
doi:
Substances chimiques
KRAS protein, human
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
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
663-678.e8Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL128172
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL134745
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA196408
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL134766
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122442
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL095993
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL150876
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests W.D.W. is a member of the Leica Biosystems Medical Imaging Advisory Board. S.M.D. is on the Scientific Advisory Boards of EarlyDiagnostics; Johnson & Johnson Lung Cancer Initiative; LungLife AI; and T-Cure Bioscience. He has received research funding from Johnson & Johnson Lung Cancer Initiative and Novartis. C.F.K. has a sponsored research agreement from Celgene/BMS, but this funding did not support the research described in this manuscript.
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