Using hESC-Derived Lung Cells to Study the Initiation of Small Cell Lung Cancer
Technical Report,15 Jun 2017,14 Jun 2018
Weill Medical College of Cornell University New York United States
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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. In research supported by this award, we have exploited our recent discovery that up to 10 percent of lung progenitor cells derived from hESCs can be induced by inhibition of NOTCH signaling to form pulmonary neuroendocrine cells PNECs, the putative precursors to small cell lung cancers SCLCs. 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. However, similarly reducing levels of TP53 protein, the product of another tumor suppressor gene commonly mutated in SCLCs, or expressing mutant KRAS or EGFR genes, commonly implicated in lung adenocarcinomas, did not induce or expand PNECs, consistent with lineage-specific sensitivity to loss of RB function. Still, 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, implying distinct functional requirements for down-modulation of both tumor suppressor genes. 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 demonstrate that genetic manipulation of hESC-derived pulmonary cells permits a detailed analysis of steps involved in the initiation, progression, and treatment of this recalcitrant cancer.
- Medicine and Medical Research
- Anatomy and Physiology