SUMMARYBy 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.ABSTRACTCell 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.
We recently described the synthetic lethality that results when mutant KRAS and mutant EGFR are coexpressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for the mutual exclusivity of KRAS and EGFR mutations in lung cancers. We have now further defined the biochemical events responsible for the toxic effects of signaling through the RAS pathway. By combining pharmacological and genetic approaches, we have developed multiple lines of evidence that signaling through extracellular signalregulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes that drive signaling through the RAS pathway must restrain the activity of ERK1/2 to avoid cell toxicities and enable tumor growth. In particular, a dual specificity phosphatase, DUSP6, regulates phosphorylated (P)-ERK levels in lung adenocarcinoma cells, providing negative feedback to the RAS signaling pathway. Accordingly, inhibition of DUSP6 is cytotoxic in LUAD cells driven by either mutant KRAS or mutant EGFR, phenocopying the effects of co-expression of mutant KRAS and EGFR. Together, these data suggest that targeting DUSP6 or other feedback regulators of the EGFR-KRAS-ERK pathway may offer a strategy for treating certain cancers by exceeding an upper threshold of RAS-mediated signaling.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.