New model sheds light on how small cell lung cancer is initiated

By Sally Robertson, B.Sc.Feb 11 2019

Scientists from Weill Cornell Medicine have developed a stem-cell-based model of small cell lung cancer that will help them understand how the disease is initiated and how it progresses.

Shutterstock | David Litman

The model has already enabled lead author Joyce Chen and colleagues to make an important discovery about two tumor suppressor genes that are often mutated in this highly aggressive and lethal form of lung cancer.

Small cell lung cancer is a disease that is almost exclusive to smokers. Generally, it becomes resistant to treatments such as chemotherapy within just several months. Despite attempts to develop new treatments, little progress has been made and eventually the US Congress and National Cancer Institute categorized the disease as a "recalcitrant" cancer.

The cancer is thought to arise from a specific subset of lung cells called pulmonary neuroendocrine cells (PNECs). However, researchers have not known how to make human embryonic stem cells differentiate into PNECs.

Now, Chen says: "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."

Virtually all patients with small cell lung cancer have mutations in the tumor suppressor genes RB and TP53. Chen and colleagues have now found that lung progenitor cells form more PNECs when the RB gene is inhibited and that those PNECs express a gene set that closely resembles the one seen in early-stage SCLC tumors.

Next, the researchers inhibited TP53, which caused  he PNECs to start expressing genes that promote cell growth and stop cell death. After culturing these PNECs, the team intravenously administered them to mice.

As reported in the Journal of Experimental Medicine, Chen and colleagues found that the PNECS slowly started to form tumors in the animals, suggesting that it is mutations in RB and TP53 that influence disease initiation.  

"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," says co-lead author Harold Varmus. "If so, it should be possible to test cells at different stages of tumor development for susceptibility and resistance to therapeutic strategies."