How one type of lung cancer can turn into another

Lung tumors called adenocarcinomas sometimes respond to initially effective treatments by transforming into much more aggressive small cell lung cancer (SCLC) that spreads quickly and offers few treatment options. Weill Cornell Medicine researchers have developed a mouse model that sheds light on this problematic process, known as histological transformation. The findings advance understanding of how mutated genes can trigger cancer progression and suggest targets for more effective treatments.

The researchers, whose results were published on February 8 in Sciencefound that during the transition from lung adenocarcinoma to small cell lung cancer (SCLC), mutated cells appeared to undergo a change in cellular identity via an intermediate stem cell-like state, which facilitated the transformation.

“It is very difficult to study this process in human patients, so my goal was to discover the mechanism underlying the transformation of lung adenocarcinoma into small cell lung cancer in a mouse model,” said Dr. Eric Gardner, postdoctoral researcher and study leader. the laboratory of Dr. Harold Varmus, professor of medicine at Lewis Thomas University and 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 allowed researchers to solve this difficult problem.

This study was carried out in collaboration with Dr. Ashley Laughney, assistant professor of physiology and biophysics and member of the Meyer Cancer Center at Weill Cornell Medicine, and Ethan Earlie, graduate student in the Laughney laboratory and member of the Tri-Institutional Computational Biology and Computational Biology Program. medicine.

“It is well known that cancer cells continue to evolve, in part to escape the pressure of effective treatments,” Dr Varmus said. “This study shows how new technologies, including detection of molecular characteristics of unique cancer cells, combined with computational data analysis, can describe dramatic and complex events in the evolution of deadly cancers, thereby exposing new drug targets. “therapeutic attack.”

Take the transformation in the act

SCLC occurs most often in heavy smokers, but this type of tumor also develops in a significant number of patients with lung adenocarcinomas, particularly after treatment with therapies targeting a protein called epidermal growth factor receptor (EGFR), which promotes tumor growth. New SCLC-like tumors are resistant to anti-EGFR treatment because their growth is fueled by a new cancer driver, namely high levels of Myc protein.

To untangle the interplay of these cancer pathways, the researchers engineered mice to develop a common form of lung adenocarcinoma, in which lung epithelial cells are driven by a mutated version of the EGFR gene. They then transformed the adenocarcinoma tumors into SCLC-like tumors, which usually arise from neuroendocrine cells. They did this by shutting down EGFR in the presence of several other changes, including loss of the tumor suppressor genes Rb1 and Trp53, as well as increasing production of Myc, a known driver of SCLC.

Oncogenes, such as EGFR and Myc, are mutated forms of genes that normally control cell growth. They are known for their role in the growth and spread of cancer. Tumor suppressor genes, on the other hand, normally inhibit cell proliferation and tumor development.

Context matters

Surprisingly, this study showed that oncogenes act in a context-dependent manner. While most lung cells are resistant to Myc-induced cancer, neuroendocrine cells are very sensitive to the oncogenic effects of Myc. Conversely, epithelial cells, which line the air sacs of the lungs and are the precursors to lung adenocarcinomas, grow excessively in response to mutated EGFR.

“This shows that an ‘oncogene’ in the wrong cell type no longer acts as an oncogene,” Dr. Laughney said. “So this fundamentally changes the way we think about oncogenes.”

The researchers also discovered a stem cell-like intermediate that was neither adenocarcinoma nor SCLC. Cells in this transitional state only became neuroendocrine in nature when mutations in the tumor suppressor genes RB1 and TP53 were present. They observed that the loss of another tumor suppressor called Pten accelerated this process. At this point, oncogenic Myc could drive these intermediate stem cells to form SCLC-like tumors.

This study further supports efforts to seek treatments targeting Myc proteins, which are involved in many types of cancers. The researchers now plan to use their new mouse model to further explore the adenocarcinoma-SCLC transition, detailing, for example, how the immune system normally responds to this transition.