Multiple cells-of-origin of mutant K-Ras–induced mouse lung adenocarcinoma
Menée à l'aide d'un modèle murin d'adénocarcinome pulmonaire induit par un gène K-Ras muté, cette étude montre qu'il existe plusieurs voies cellulaires menant à la formation d'une tumeur et que la cellule d'origine en influence le phénotype histologique
Much controversy surrounds the cell-of-origin of mutant K-Ras (K-RasG12D)–induced lung adenocarcinoma. To shed light on this issue, we have used technology that enables us to conditionally target K-RasG12D expression in Surfactant Protein C (SPC)+ alveolar type 2 cells and in Clara cell antigen 10 (CC10)+ Clara cells by use of cell-type–restricted recombinant Adeno-Cre viruses. Experiments were performed both in the presence and absence of the tumor suppressor gene p53, enabling us to assess what effect the cell-of-origin and the introduced genetic lesions have on the phenotypic characteristics of the resulting adenocarcinomas. We conclude that both SPC-expressing alveolar type 2 cells and CC10-expressing Clara cells have the ability to initiate malignant transformation following the introduction of these genetic alterations. The lungs of K-Raslox–Stop–lox–G12D/+ and K-Raslox–Stop–lox–G12D/+;tumor suppressor gene Trp53F/F mice infected with Adeno5–SPC–Cre and Adeno5–CC10–Cre viruses displayed differences in their tumor spectrum, indicating distinct cellular routes of tumor initiation. Moreover, using a multicolor Cre reporter line, we demonstrate that the resulting tumors arise from a clonal expansion of switched cells. Taken together, these results indicate that there are multiple cellular paths to K-RasG12D–induced adenocarcinoma and that the initiating cell influences the histopathological phenotype of the tumors that arise.