An organoid library unveils subtype-specific IGF-1 dependency via a YAP-AP1 axis in human small cell lung cancer
Takahiro Fukushima1, Kazuhiro Togasaki2,3,4, Junko Hamamoto1
1Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
Abstract:
Small cell lung cancer (SCLC) is a devastating disease with limited therapeutic advancements. Although SCLC has recently been classified into four molecular subtypes, subtype-specific therapies are still lacking. Here, we established 40 patient-derived SCLC organoid lines with predominant TP53 and RB1 alterations and rare targetable genetic lesions. Transcriptome profiling divided the SCLC organoids into neuroendocrine (NE)-type SCLC and non-NE-type SCLC, with the latter characterized by YAP1 or POU2F3 expression. NE-type SCLC organoids grew independent of alveolar niche factors, whereas non-NE-type SCLC organoids relied on insulin-like growth factor (IGF)-1-driven YAP1 and AP1 activation. Therapeutic targeting of IGF-1, YAP1 and AP1 effectively suppressed the growth of non-NE-type organoids. Co-knockout of TP53 and RB1 in human alveolar cells altered their lineage toward the airway epithelium-like fate and conferred IGF-1 dependency, validating the subtype-phenotype connection. Our SCLC organoid library represents a valuable resource for developing biology-based therapies and has the potential to reshape the drug discovery landscape.
Insights
Researchers developed 40 small cell lung cancer (SCLC) organoid models. Targeting insulin-like growth factor-1 (IGF-1) and YAP1 pathways suppressed non-neuroendocrine SCLC growth, offering new therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Small cell lung cancer (SCLC) presents limited therapeutic options despite molecular subtype classification.
- Subtype-specific treatments for SCLC remain largely undeveloped.
- Patient-derived organoids offer a promising model for studying cancer heterogeneity.
Purpose of the Study:
- To establish and characterize patient-derived SCLC organoid lines.
- To identify molecular drivers and dependencies of different SCLC subtypes.
- To explore targeted therapeutic strategies for non-neuroendocrine SCLC.
Main Methods:
- Generation of 40 patient-derived SCLC organoid lines.
- Transcriptome profiling to classify SCLC subtypes.
- In vitro validation of therapeutic targets (IGF-1, YAP1, AP1).
- Genetic manipulation of human alveolar cells to validate subtype-phenotype connections.
Main Results:
- SCLC organoids classified into neuroendocrine (NE) and non-NE subtypes.
- Non-NE SCLC characterized by YAP1 or POU2F3 expression and dependency on IGF-1 signaling.
- Targeting IGF-1, YAP1, and AP1 pathways inhibited non-NE SCLC organoid growth.
- TP53/RB1 alterations in alveolar cells induced airway epithelium-like fate and IGF-1 dependency.
Conclusions:
- The established SCLC organoid library is a valuable resource for SCLC research.
- Non-NE SCLC subtypes exhibit specific dependencies that can be therapeutically targeted.
- Understanding SCLC subtype biology can reshape drug discovery and lead to novel therapies.
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