Small cell lung cancer (SCLC) remains a major challenge in public health because of its frequency, its lethality, and the paucity of convenient models for exploring its pathogenesis and potential therapeutic vulnerabilities. Despite recent research advances, fundamental features of SCLC, especially its initiation and progression, are not fully understood. One of the main obstacles is the development of a feasible and tractable system that allows molecular events to be evaluated for their functional changes towards the hallmarks of neoplasia during lung lineage differentiation.
To understand how and why certain constellations of genetic changes drive carcinogenesis in specialized human cell lineages, we are developing cell culture models based on directed differentiation of human embryonic stem cells (hESCs). In this report, we show for the first time 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 SCLCs, by inhibition of NOTCH signaling. In such cultures, reduction of the retinoblastoma (RB) protein, the product of a tumor suppression gene commonly mutated in SCLCs, significantly expanded the number of PNECs. But reduction of TP53 protein, the product of another tumor suppressor gene uniformly mutated in SCLCs, or expression of mutant KRAS or EGFR genes, each of which is commonly found in human lung adenocarcinomas, did not induce or expand PNECs, suggesting a lineage-specific sensitivity to loss of RB function. Subcutaneous injection of PNEC-containing cultures in which expression of both RB and TP53 was blocked produced tumors resembling early stage SCLC in immunodeficient mice. Single-cell RNA profiles of PNECs were heterogeneous; when RB levels are reduced, the profiles show similarities to RNA profiles from early stage SCLC. 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.
Dr.Huanhuan Joyce Chen has received her Pharm.D. degree in Pharmaceutical Sciences at Zhejiang University in China, M.S. and Ph.D. degrees in Biomedical Engineering at Cornell University. She will be enrolled as an Assistant Professor in Pritzker School of molecular engineering and the Ben May department for cancer research at The University of Chicago in May 2020, and is currently a postdoctoral fellow with Dr. Harold Varmus at Weill Cornell Medicine. She received a number of awards including NIH Pathway to Independence Award (K99/R00), Arnold O. Beckman Postdoctoral Fellowship, National Cancer Institute Physical Sciences in Oncology Young Investigator award and National Science Foundation Graduate Research Fellowship. She has published more than 19 papers in reputed journals, including Nature Biotechnology, Nature Medicine, Nature Communication, Cell Stem Cell, Journal of Experimental Medicine, Journal of Clinical Investigation, Lab on Chip and eLife. Her research is focused on stem cell technology and tissue engineering for modeling and studying cell biology and genetic diseases.