Oncogenic Kras reverts differentiated cells back into alveolar stem cells that generate lepidic adenocarcinoma

• Published in: Nature (London) 2023-07, Vol.619 (7971), p.860-867
• Main Authors: Juul, Nicholas H., Yoon, Jung-Ki, Martinez, Marina C., Rishi, Neha, Kazadaeva, Yana I., Morri, Maurizio, Neff, Norma F., Trope, Winston L., Shrager, Joseph B., Sinha, Rahul, Desai, Tushar J.
• Format: Article
• Language: English
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06324-w

Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by rapid adenomatous transformation of pulmonary alveolar type II (AT2) cells. Here, we demonstrate a different scenario: expression of KrasG12D in fully differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 cells that go on to generate indolent tumors. Like human lepidic adenocarcinoma, the tumor cells slowly spread along intact alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant Wnt activation and KrasG12D induction, which dramatically increases AT2-derived but inhibits AT1-derived adenoma proliferation. Pharmacological augmentation of ERK activity in KrasG12D-induced AT1 cells dramatically increases transformation efficiency, proliferation, and likelihood of progression from pure lepidic to mixed tumor histology. Overall, we have identified a novel cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic Kras to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer’s current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behavior. Oncogenic Kras reprograms differentiated AT1 cells into AT2 cells that generate indolent and functionally constrained tumors that share features with human lepidic lung adenocarcinoma.