Basal extrusion of single‐oncogenic mutant cells induces dome‐like structures with altered microenvironments

• Published in: Cancer science 2022-11, Vol.113 (11), p.3710-3721
• Main Authors: Shirai, Takanobu, Sekai, Miho, Kozawa, Kei, Sato, Nanami, Tanimura, Nobuyuki, Kon, Shunsuke, Matsumoto, Tomohiro, Murakami, Takeru, Ito, Shoko, Tilston‐Lunel, Andrew, Varelas, Xaralabos, Fujita, Yasuyuki
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibodies; Cancer; Carcinogenesis; Cell Transformation, Neoplastic - metabolism; Cytokeratin; Dogs; dome‐like structure; Epithelial cells; Epithelial Cells - pathology; epithelial–mesenchymal transition; Epithelium; Epithelium - metabolism; Fibroblasts; Genotype & phenotype; Ibuprofen; initial stage of carcinogenesis; Keratin; Macrophages; Madin Darby Canine Kidney Cells; Mesenchyme; Mice; Mutants; Nonsteroidal anti-inflammatory drugs; Oncogenes; Original; Pancreas; RasV12; Transformed cells; Tumor Microenvironment
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15483

At the initial stage of carcinogenesis, oncogenic transformation occurs in single cells within epithelial layers. However, the behavior and fate of the newly emerging transformed cells remain enigmatic. Here, using originally established mouse models, we investigate the fate of RasV12‐transformed cells that appear in a mosaic manner within epithelial tissues. In the lung bronchial epithelium, most majority of RasV12‐transformed cells are apically extruded, whereas noneliminated RasV12 cells are often basally delaminated leading to various noncell‐autonomous changes in surrounding environments; macrophages and activated fibroblasts are accumulated, and normal epithelial cells overlying RasV12 cells overproliferate and form a convex multilayer, which is termed a ‘dome‐like structure’. In addition, basally extruded RasV12 cells acquire certain features of epithelial–mesenchymal transition (EMT). Furthermore, the expression of COX‐2 is profoundly elevated in RasV12 cells in dome‐like structures, and treatment with the COX inhibitor ibuprofen suppresses the recruitment of activated fibroblasts and moderately diminishes the formation of dome‐like structures. Therefore, basal extrusion of single‐oncogenic mutant cells can induce a tumor microenvironment and EMT and generate characteristic precancerous lesions, providing molecular insights into the earlier steps of cancer development. Dome‐like tumor microenvironment around basally extruded RasV12‐transformed cells in the bronchial epitheilum