Cooperative pro-tumorigenic adaptation to oncogenic RAS through epithelial-to-mesenchymal plasticity.
Hadrien De BlanderLaurie TononFrédérique FauvetRoxane M PommierChristelle LamblotRahma BenhassounFrancesca AngileriBenjamin GibertRaphaël RodriguezMaria OuzounovaAnne-Pierre MorelAlain PuisieuxPublished in: Science advances (2024)
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.
Keyphrases
- wild type
- signaling pathway
- stem cells
- endothelial cells
- bone marrow
- epithelial mesenchymal transition
- induced apoptosis
- pi k akt
- dna damage
- high glucose
- anti inflammatory
- transcription factor
- magnetic resonance
- oxidative stress
- long non coding rna
- poor prognosis
- gene expression
- cell cycle arrest
- magnetic resonance imaging
- big data
- machine learning
- diabetic rats
- cell death
- endoplasmic reticulum stress
- computed tomography
- pluripotent stem cells