Cooperative pro-tumorigenic adaptation to oncogenic RAS through epithelial-to-mesenchymal plasticity

• Published in: Science advances Vol. 10; no. 7; p. eadi1736
• Main Authors: De Blander, Hadrien, Tonon, Laurie, Fauvet, Frédérique, Pommier, Roxane M, Lamblot, Christelle, Benhassoun, Rahma, Angileri, Francesca, Gibert, Benjamin, Rodriguez, Raphaël, Ouzounova, Maria, Morel, Anne-Pierre, Puisieux, Alain
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 16.02.2024; American Association for the Advancement of Science
• Subjects: Biomedicine and Life Sciences; Breast; Cancer; Carcinogenesis - genetics; Cell Biology; Cell Transformation, Neoplastic - genetics; Cellular Senescence - genetics; Genes, ras; Humans; Life Sciences; SciAdv r-articles; Signal Transduction; Tumor Microenvironment
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adi1736

In breast cancers, aberrant activation of the RAS/MAPK pathway is strongly associated with mesenchymal features and stemness traits, suggesting an interplay between this mitogenic signaling pathway and epithelial-to-mesenchymal plasticity (EMP). By using inducible models of human mammary epithelial cells, we demonstrate herein that the oncogenic activation of RAS promotes ZEB1-dependent EMP, which is necessary for malignant transformation. Notably, EMP is triggered by the secretion of pro-inflammatory cytokines from neighboring RAS-activated senescent cells, with a prominent role for IL-6 and IL-1α. Our data contrast with the common view of cellular senescence as a tumor-suppressive mechanism and EMP as a process promoting late stages of tumor progression in response to signals from the tumor microenvironment. We highlighted here a pro-tumorigenic cooperation of RAS-activated mammary epithelial cells, which leverages on oncogene-induced senescence and EMP to trigger cellular reprogramming and malignant transformation.