Lung tumors called adenocarcinomas sometimes respond to initially effective treatments by transforming into a much more aggressive small cell lung cancer (SCLC) that spreads quickly and has few treatment options. 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 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), the mutated cells appeared to undergo a change in cellular identity through an intermediate stem cell-like state, facilitating 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 to small cell lung cancer in a mouse model,” said study leader Dr. Eric Gardner, a postdoctoral fellow in Dr. Harold Varmus, professor at Lewis Thomas University. of Medicine 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 has allowed researchers to solve this difficult problem.
This study was conducted 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, a graduate student in Laughney’s 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 characteristics of individual cancer cells, combined with computer analysis of the data, can represent dramatic and complex events in the evolution of lethal cancers, exposing new targets for therapeutic attack “.
Capture the transformation in the act
SCLC occurs most frequently 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), that promotes tumor growth. The new SCLC-type tumors are resistant to anti-EGFR therapy because their growth is driven by a new cancer factor: high levels of the Myc protein.
To unravel the interplay of these cancer pathways, 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 converted the adenocarcinoma tumors into SCLC-type tumors, which usually arise from neuroendocrine cells. They did it by closing EGFR in the presence of several other changes, including losses of tumor suppressor genes Rb1 and Trp53 In addition to increasing the production of Myc, a known SCLC driver.
Oncogenes like EGFR and My c, are mutated forms of genes that normally control cell growth. They are known for their role in driving the growth and spread of cancer. Tumor suppressor genes, on the other hand, normally inhibit cell proliferation and tumor development.
Surprisingly, this study demonstrated that oncogenes act in a context-dependent manner. Although most lung cells are resistant to becoming cancerous due to My cneuroendocrine cells, are very sensitive to the oncogenic effects of My c. In contrast, epithelial cells, which line the alveoli of the lungs and are precursors to lung adenocarcinomas, grow excessively in response to mutations. EGFR.
“This shows that an ‘oncogene’ in the wrong cell type no longer acts as an oncogene,” Dr. Laughney said. “So it 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 transition state acquired neuroendocrine nature only when mutations occurred in tumor suppressor genes. RB1 and TP53 They were present. They observed that the loss of another tumor suppressor called pten accelerated this process. At that stage, oncogenic My c could drive these intermediate stem cells to form SCLC-type tumors.
This study further supports efforts seeking therapies targeting Myc proteins, which are implicated in many types of cancers. The researchers now plan to use their new mouse model to further explore the transition between adenocarcinoma and SCLC, detailing, for example, how the immune system normally responds to this transition.
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