Lineage-specific intolerance to oncogenic drivers restricts histological transformation

• DOI: 10.1126/science.adj1415
• Publication Date: 2024-02-08T19:01:35Z
• Authors: Eric E. Gardner; Ethan M. Earlie; Kate Li; Jerin Thomas; Melissa J. Hubisz; Benjamin D. Stein; Chen Zhang; Lewis C. Cantley; Ashley M. Laughney; Harold Varmus
• Keywords: Lineage (genetic); Basal (medicine); Cell of origin; Malignant Transformation; Neuroendocrine differentiation

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