Lineage-specific intolerance to oncogenic drivers restricts histological transformation

• 成果类型: Article
• 署名作者: Gardner, Eric E.; Earlie, Ethan M.; Li, Kate; Thomas, Jerin; Hubisz, Melissa J.; Stein, Benjamin D.; Zhang, Chen; Cantley, Lewis C.; Laughney, Ashley M.; Varmus, Harold
• 署名单位: Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard Medical School
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12054
• DOI: 10.1126/science.adj1415
• 发表日期: 2024-02-09
• 关键词: cell lung-cancer; stem-cells; basal-cells; neuroendocrine; alveolar; inactivation; expression; progenitor; mutations; EVOLUTION

摘要

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC after treatment with targeted therapies. In this study, we designed models to follow the conversion of LUAD to SCLC and found that the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells that transcriptionally resemble the pulmonary basal lineage. These findings suggest that histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.