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Updated: Aug 6, 2026
Generation of 3D Whole Lung Organoids from Induced Pluripotent Stem Cells for Modeling Lung Developmental Biology and Disease
Published on: April 12, 2021
Generation of a distal lung cancer organoid model using oncogenic ret-expressing induced pluripotent stem cells
Jin Wook Hwang1,2, Christophe Desterke1,2, Paul Marcoux1,2
1INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France.
Abstract:
The tyrosine kinase receptor RET is altered by genetic fusions in a subset of non-small cell lung cancers (NSCLCs). To determine if we can generate organoids with lung cancer features in this context, we used two iPSC lines overexpressing oncogenic RET-M918T and RET-C634Y mutations. Lung progenitor cells (LPCs) were generated after 18 days of culture, followed by air-liquid interface cultures giving rise to alveolar structures expressing SFTPC, TTF-1, MUC1, and CK5/6 at day +38. Transplantation of LPCs into NOD/SCID mice generated tumors harboring bronchial structures, ciliated cells, goblet cells, and the squamous cell carcinoma marker p40. Single-cell RNA sequencing analyses allowed us to determine the major genes involved with response or resistance to Selpercatinib, a major inhibitor targeting RET-altered lung cancers. These findings show that the iPSC-derived preclinical model can recapitulate some features of NSCLC and has significant potential for identifying new therapeutic targets in RET-inhibitor-refractory lung cancers.
Insights
Researchers developed a new preclinical model using induced pluripotent stem cells (iPSCs) to study RET-altered non-small cell lung cancer (NSCLC). This model helps identify therapeutic targets for lung cancer resistant to RET inhibitors.
Area of Science:
- Oncology
- Stem Cell Biology
- Genetics
Background:
- Genetic alterations in the tyrosine kinase receptor RET are implicated in a subset of non-small cell lung cancers (NSCLCs).
- Developing effective preclinical models is crucial for understanding NSCLC pathogenesis and identifying novel therapeutic strategies.
Purpose of the Study:
- To generate organoids with lung cancer features from iPSC lines harboring oncogenic RET mutations.
- To establish a preclinical model for studying RET-altered NSCLC and identifying therapeutic targets.
Main Methods:
- Utilized two iPSC lines with RET-M918T and RET-C634Y mutations.
- Generated lung progenitor cells (LPCs) and cultured them using air-liquid interface.
- Transplanted LPCs into NOD/SCID mice to form tumors.
- Performed single-cell RNA sequencing to analyze gene expression related to drug response.
Main Results:
- Generated alveolar structures expressing key lung markers (SFTPC, TTF-1, MUC1, CK5/6).
- Transplanted LPCs formed tumors with bronchial structures and differentiated cell types, including squamous cell carcinoma markers.
- Identified major genes involved in response and resistance to Selpercatinib using single-cell RNA sequencing.
Conclusions:
- The iPSC-derived preclinical model effectively recapitulates key features of NSCLC.
- This model shows significant potential for identifying new therapeutic targets in RET-inhibitor-refractory lung cancers.
