Definitive evidence for Club cells as progenitors for mutant Kras/Trp53‐deficient lung cancer

Abstract Accumulating evidence suggests that both the nature of oncogenic lesions and the cell‐of‐origin can strongly influence cancer histopathology, tumor aggressiveness and response to therapy. Although oncogenic Kras expression and loss of Trp53 tumor suppressor gene function have been demonstrated to initiate murine lung adenocarcinomas (LUADs) in alveolar type II (AT2) cells, clear evidence that Club cells, representing the second major subset of lung epithelial cells, can also act as cells‐of‐origin for LUAD is lacking. Equally, the exact anatomic location of Club cells that are susceptible to Kras transformation and the resulting tumor histotype remains to be established. Here, we provide definitive evidence for Club cells as progenitors for LUAD. Using in vivo lineage tracing, we find that a subset of Kras 12V ‐expressing and Trp53‐ deficient Club cells act as precursors for LUAD and we define the stepwise trajectory of Club cell‐initiated tumors leading to lineage marker conversion and aggressive LUAD. Our results establish Club cells as cells‐of‐origin for LUAD and demonstrate that Club cell‐initiated tumors have the potential to develop aggressive LUAD.