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Updated: Dec 9, 2025

Generation of 3D Whole Lung Organoids from Induced Pluripotent Stem Cells for Modeling Lung Developmental Biology and Disease
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Generation of 3D Whole Lung Organoids from Induced Pluripotent Stem Cells for Modeling Lung Developmental Biology and Disease

Published on: April 12, 2021

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Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells

Antonella F M Dost1, Aaron L Moye1, Marall Vedaie2

  • 1Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Cell Stem Cell
|September 6, 2020
PubMed

Insights

Activating KRAS mutations in epithelial cancers cause early molecular changes. Our study used organoid models to show oncogenic KRAS reduces mature cell identity genes in lung adenocarcinoma progenitor cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mutant KRAS is a key driver in many epithelial cancers.
  • Early molecular events following oncogenic KRAS activation are not well understood.
  • Understanding these early changes is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the early transcriptional consequences of oncogenic KRAS activation in epithelial cells.
  • To develop and validate organoid models for studying early-stage lung adenocarcinoma.
  • To identify molecular changes distinguishing normal progenitor cells from early cancer cells.

Main Methods:

  • Single-cell RNA sequencing to analyze transcriptional changes.
  • Comparison across four distinct sample sets: patient samples, mouse models, and two organoid systems (mouse and human iPSC-derived).
  • Development of in vitro organoid models from lung epithelial progenitor cells.

Main Results:

  • Consistent transcriptional alterations were observed across all four tested settings.
  • Alveolar epithelial progenitor (AT2) cells with oncogenic KRAS showed decreased expression of mature lineage identity genes.
  • The study generated extensive datasets and organoid tools for further research.

Conclusions:

  • In vitro organoid models are effective for studying early oncogenic KRAS effects.
  • Oncogenic KRAS activation impacts epithelial progenitor cell identity.
  • This work provides resources to identify therapeutic targets for KRAS-driven cancers.
Keywords:
KRASalveolardevelopmental programsearly-stage lung canceriPSCloss of differentiationorganoidsingle-cell RNA sequencingstage IA lung adenocarcinomatumor progression

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