Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells.

TitleGeneration of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells.
Publication TypeJournal Article
Year of Publication2019
AuthorsChen HJoyce, Poran A, Unni AM, Huang SXuelian, Elemento O, Snoeck H-W, Varmus H
JournalJ Exp Med
Date Published2019 03 04
KeywordsAnimals, ErbB Receptors, Gene Expression Regulation, Neoplastic, Human Embryonic Stem Cells, Humans, Lung, Lung Neoplasms, Mice, Inbred NOD, Neuroendocrine Cells, Proto-Oncogene Proteins p21(ras), Receptors, Notch, Retinoblastoma Protein, Single-Cell Analysis, Small Cell Lung Carcinoma, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays

Cancer models based on cells derived from human embryonic stem cells (hESCs) may reveal why certain constellations of genetic changes drive carcinogenesis in specialized lineages. Here we demonstrate that inhibition of NOTCH signaling induces up to 10% of lung progenitor cells to form pulmonary neuroendocrine cells (PNECs), putative precursors to small cell lung cancers (SCLCs), and we can increase PNECs by reducing levels of retinoblastoma (RB) proteins with inhibitory RNA. Reducing levels of TP53 protein or expressing mutant or genes did not induce or expand PNECs, but tumors resembling early-stage SCLC grew in immunodeficient mice after subcutaneous injection of PNEC-containing cultures in which expression of both and was blocked. Single-cell RNA profiles of PNECs are heterogeneous; when RB levels are reduced, the profiles resemble those from early-stage SCLC; and when both RB and TP53 levels are reduced, the transcriptome is enriched with cell cycle-specific RNAs. Our findings suggest that genetic manipulation of hESC-derived pulmonary cells will enable studies of this recalcitrant cancer.

Alternate JournalJ. Exp. Med.
PubMed ID30737256
PubMed Central IDPMC6400536
Grant ListU01 CA224326 / CA / NCI NIH HHS / United States