Modeling RET-Rearranged Non-Small Cell Lung Cancer (NSCLC): Generation of Lung Progenitor Cells (LPCs) from Patient-Derived Induced Pluripotent Stem Cells (iPSCs)

• Published in: Cells (Basel, Switzerland) Switzerland), 2023-12, Vol.12 (24), p.2847
• Main Authors: Marcoux, Paul, Hwang, Jin Wook, Desterke, Christophe, Imeri, Jusuf, Bennaceur-Griscelli, Annelise, Turhan, Ali G
• Format: Article
• Language: English
• Subjects: cancer; Drug resistance; Drug screening; Genetic variability; Inhibitory postsynaptic potentials; iPSCs; Kinases; Ligands; LPC differentiation; Lung cancer; Medical prognosis; Molecular modelling; Mutation; Non-small cell lung carcinoma; NSCLC; patient derived; Patients; Pluripotency; Progenitor cells; RET; Small cell lung carcinoma; Stem cells; Therapeutic targets; Thyroid carcinoma; Transcriptomics; Transfection; Tumors
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12242847

REarranged during Transfection (RET) oncogenic rearrangements can occur in 1-2% of lung adenocarcinomas. While RET-driven NSCLC models have been developed using various approaches, no model based on patient-derived induced pluripotent stem cells (iPSCs) has yet been described. Patient-derived iPSCs hold great promise for disease modeling and drug screening. However, generating iPSCs with specific oncogenic drivers, like rearrangements, presents challenges due to reprogramming efficiency and genotypic variability within tumors. To address this issue, we aimed to generate lung progenitor cells (LPCs) from patient-derived iPSCs carrying the mutation , commonly associated with medullary thyroid carcinoma. Additionally, we established a knock-in iPSC model to validate the effect of this oncogenic mutation during LPC differentiation. We successfully generated LPCs from iPSCs using a 16-day protocol and detected an overexpression of cancer-associated markers as compared to control iPSCs. Transcriptomic analysis revealed a distinct signature of NSCLC tumor repression, suggesting a lung multilineage lung dedifferentiation, along with an upregulated signature associated with mutation, potentially linked to poor NSCLC prognosis. These findings were validated using the knock-in iPSC model, highlighting key cancerous targets such as and , known to be associated with poor prognostic outcomes. Furthermore, the LPCs derived from iPSCs exhibited a positive response to the RET inhibitor pralsetinib, evidenced by the downregulation of the cancer markers. This study provides a novel patient-derived off-the-shelf iPSC model of RET-driven NSCLC, paving the way for exploring the molecular mechanisms involved in RET-driven NSCLC to study disease progression and to uncover potential therapeutic targets.