Summary
Weill Cornell Medicine scientists create a mouse model to study lung cancer’s transformation into deadly SCLC.
Lung tumors called adenocarcinomas sometimes respond to initially effective treatments by transforming into a much more aggressive small cell lung cancer (SCLC) that spreads rapidly and has few options for treatment. Researchers at Weill Cornell Medicine have developed a mouse model that illuminates this problematic process, known as histological transformation. The findings advance the understanding of how mutated genes can trigger cancer evolution and suggest targets for more effective treatments.
The researchers, whose results were published Feb. 8 in Science, discovered that during the transition from lung adenocarcinoma to small cell lung cancer (SCLC), the mutated cells appeared to undergo a change in cell identity through an intermediate, stem cell-like state, which facilitated the transformation.
“It is very difficult to study this process in human patients. So my aim was to uncover the mechanism underlying the transformation of lung adenocarcinoma to small cell lung cancer in a mouse model,” said study lead Dr. Eric Gardner, a postdoctoral fellow in the laboratory of Dr. Harold Varmus, the Lewis Thomas University Professor of Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. The complex mouse model took several years to develop and characterize but has allowed the researchers to crack this difficult problem.
This study was in collaboration with Dr. Ashley Laughney, assistant professor of physiology and biophysics and a member of the Meyer Cancer Center at Weill Cornell Medicine and Ethan Earlie, a graduate student in the Laughney lab and part of the Tri-Institutional Computational Biology and Medicine program.
“It is well known that cancer cells continue to evolve, especially to escape the pressure of effective treatments,” said Dr. Varmus. “This study shows how new technologies—including the detection of molecular features of single cancer cells, combined with computer-based analysis of the data—can portray dramatic, complex events in the evolution of lethal cancers, exposing new targets for therapeutic attack.”
Catching Transformation in the Act
SCLC most commonly occurs in heavy smokers, but this type of tumor also develops in a significant number of patients with lung adenocarcinomas, particularly after treatment with therapies that target a protein called Epidermal Growth Factor Receptor (EGFR), which promotes tumor growth. The new SCLC-type tumors are resistant to anti-EGFR therapy because their growth is fueled by a new cancer driver, high levels of Myc protein.
