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Developmental Biology - Embyronic Stem Cells

SMLC and Embryos

Researchers develop human cell-based model for the study of small cell lung cancer...


Researchers from Weill Cornell Medicine have used human embryonic stem cells to create a new model system that allows them to study the initiation and progression of small cell lung cancer (SCLC). The study, published February 8 in the Journal of Experimental Medicine (JEM), reveals the distinct roles played by two critical tumor suppressor genes that are commonly mutated in these highly lethal cancers.
Results suggest that mutations in the tumor suppressor genes RB and TP53 appear to initiate small cell lung cancer or SCLC:

• lung progenitor cells form more PNECs when the RB gene is inhibited

• more PNEC cell expression promotes cell proliferation while preventing cell death

SCLC, an extremely aggressive form of lung cancer, is found almost exclusively in smokers and usually becomes resistant within several months to existing treatments, such as chemo- and radiotherapy. Over the last 30 years, little progress has been made in developing new treatments for the disease, causing the US Congress and National Cancer Institute to designate it as a "recalcitrant" cancer.

One reason for the lack of new treatments is the rapid onset and progression of SCLC, making it difficult to obtain clinical samples for researchers to study. Over the past few years, models for studying SCLC have been developed in mice. The authors of the new report describe an alternative way to study SCLC.

SCLS can be studied in human cells by growing embryonic stem cells in culture and differentiating them into various types of lung cells capable of becoming cancerous. SCLC is thought to develop from a particular type of lung cell, called pulmonary neuroendocrine cells (PNECs), but until now, no one knew how to induce human embryonic stem cells to become PNECs in the lab.
"We discovered a means to induce pulmonary neuroendocrine-like cells from cultured human embryonic stem cells after first differentiating them into lung progenitor cells. We did this by blocking an important cell signaling pathway known as the NOTCH pathway."

Huanhuan Joyce Chen, postdoctoral fellow, Meyer Cancer Center, Weill Cornell Medicine, and one of the lead authors on the study.

Almost all patients with SCLC carry mutations that inactivate two key tumor suppressor genes called RB and TP53. Chen and colleagues found that lung progenitors formed even more PNECs when their RB gene was inhibited in addition to the NOTCH signaling pathway. Moreover, RB-deficient PNECs expressed a set of genes very similar to those expressed by early-stage SCLC tumors, although they were unable to form tumors when injected into laboratory mice.

However, when Chen and colleagues also inhibited the TP53 gene, the PNECs began to express genes that promote cell proliferation and prevent cell death, and cultures containing these PNECs formed slowly growing tumors when injected under the skin of mice. The results suggest that mutations in the RB and TP53 affect two aspects of initiation of SCLC.
"Our system should enable further studies of the progression of these early-stage tumors into invasive SCLCs that resemble the more aggressive cancers found in patients. If so, it should be possible to test cells at different stages of tumor development for susceptibility and resistance to therapeutic strategies."

Harold Varmus, co-lead author of the study and Lewis Thomas University Professor at Weill Cornell Medicine.

Abstract
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 KRAS or EGFR 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 RB and TP53 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.

Authors
Huanhuan Joyce Chen, Asaf Poran, Arun M. Unni, Sarah Xuelian Huang, Olivier Elemento, Hans-Willem Snoeck and Harold Varmus.

Acknowledgements

The authors thank Oksana Mashadova and Sukanya Goswami in the Varmus Laboratory for technical support and Eric Gardner, Dennis Fei, and John Ferrarone in the Varmus Laboratory; Yawen Chen in the Snoeck Laboratory; Rahul Satija (New York Genome Center); Viviane Tabar (Memorial Sloan-Kettering Cancer Center); and Shuibing Chen (Weill Cornell Medicine) for useful advice.

This work is supported by the US Department of Defense (award LC160136 to H. Varmus and O. Elemento); funds from the Meyer Cancer Center, Weill Cornell Medicine (to H. Varmus); an Arnold O. Beckman postdoctoral fellowship (to H.J. Chen); and a Weill Cornell graduate fellowship (to A. Poran).

The authors declare no competing financial interests.

About the Journal of Experimental Medicine The Journal of Experimental Medicine (JEM) features peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JEM makes all of its content free online no later than six months after publication. Established in 1896, JEM is published by Rockefeller University Press. For more information, visit jem.org.

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Feb 14, 2018   Fetal Timeline   Maternal Timeline   News  




Lung progenitor cells (GREEN) form increased numbers of NeuroEndocrine cells (RED)
when RB gene and NOTCH signaling pathway are shut down. Image: Chen et al., 2019.


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