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Generation of pulmonary neuro-endocrine cells and tumors resembling small cell lung cancers from human embryonic stem cells

SUMMARY By blocking an important signaling pathway (called NOTCH) and interfering with expression of two tumor suppressor genes in cells derived from human embryonic stem cells, the authors have developed a model for studying highly lethal small cell lung cancers. ABSTRACT Cell culture models based on directed differentiation of human embryonic stem cells (hESCs) may reveal why certain constellations of genetic changes drive carcinogenesis in specialized human cell lineages. Here we demonstrate that up to 10 percent of lung progenitor cells derived from hESCs can be induced to form pulmonary neuroendocrine cells (PNECs), the putative normal precursors to small cell lung cancers (SCLCs), by inhibition of NOTCH signaling. By using small inhibitory RNAs in these cultures to reduce levels of retinoblastoma (RB) protein, the product of a gene commonly mutated in SCLCs, we can significantly expand the number of PNECs. Similarly reducing levels of TP53 protein, the product of another tumor suppressor gene commonly mutated in SCLCs, or expressing mutant KRAS or EGFR genes, did not induce or expand PNECs, consistent with lineage-specific sensitivity to loss of RB function. Tumors resembling early stage SCLC grew in immunodeficient mice after subcutaneous injection of PNEC-containing cultures in which expression of both RB and TP53 was blocked. Single-cell RNA profiles of PNECs are heterogeneous; when RB levels are reduced, the profiles show similarities to RNA profiles from early stage SCLC; when both RB and TP53 levels are reduced, the transcriptome is enriched with cell cycle-specific RNAs. Taken together, these findings suggest that genetic manipulation of hESC-derived pulmonary cells will enable studies of the initiation, progression, and treatment of this recalcitrant cancer.