Summary Physical forces shape cell behavior, yet how they integrate with signaling to control fate and disease remains unclear. The alveolar epithelium is patterned by FGF signaling and mechanical stretch, but how these cues specify AT1 and AT2 cells is poorly understood. Here we show that cell membrane tension (CMT) is a conserved regulator of epithelial fate in mouse and human lungs. CMT drops before differentiation and is spatially patterned, defining where bipotent progenitors acquire AT1 or AT2 identity. Lower CMT enhances FGFR2 endocytosis and ERK signaling to drive AT2 differentiation and permits architectural remodeling that enables stretch-mediated YAP/TAZ nuclear entry for AT1 maturation. β-catenin elevates CMT cell-intrinsically independent of its role in canonical WNT transcription, while embedding, osmotic compression, or fibroblast wrapping elevate CMT extrinsically. Combined intrinsic and extrinsic tension traps alveolar epithelial cells in a KRT8⁺ transitional state seen in fibrotic lungs. Membrane tension thus integrates physical and molecular cues linking morphogenesis to fibrosis. Graphical Abstract In Brief We identify a conserved drop in cell membrane tension (CMT) that gates epithelial fate transitions across mouse and human lungs. In bipotent progenitors, reduced CMT promotes Alveolar Type 2 (AT2) fate via FGFR2 endocytosis and ERK signaling, as well as Alveolar Type 1 (AT1) fate by enabling architectural remodeling required for YAP/TAZ nuclear entry. We further show that intrinsic β-catenin and extrinsic confinement cues, including mesenchymal contact, converge to elevate CMT, restricting differentiation and—in adult AT2s—inducing a KRT8⁺ transitional state associated with fibrosis. Highlights Cell membrane tension drops before differentiation and is required for AT1 and AT2 fate acquisition. Reduced tension enhances FGFR2 endocytosis and ERK signaling to drive AT2 specification. Reduced tension permits architectural remodeling and YAP/TAZ nuclear entry required for AT1 maturation. Intrinsic β-catenin and extrinsic confinement elevate CMT to restrict differentiation and together strongly induce a KRT8⁺ transitional state associated with fibrosis.
ATRT-15. ATRTS HIJACK EPIGENETIC MECHANISMS TO PROMOTE IMMUNOSUPPRESSION AND ESCAPE FROM NK CELL THERAPY
Abstract Atypical Teratoid/Rhabdoid Tumors (ATRTs) are malignant tumors of the central nervous system in children. They are almost universally characterized by genetic loss of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin Subfamily member B1 (SMARCB1) - a core subunit of the ATP-dependent SWI/SNF chromatin remodeling complex, and dysregulation of lineage restricted enhancers. Here, we show that tumor subgroup-specific upregulation of a distant member of the transforming growth factor-β (TGF-β), bone morphogenic factor (BMF) family of proteins drives insensitivity to NK-mediated cytolysis in vitro and in vivo. Mechanistically, subgroup-specific loss of chromatin occupancy by the RE1 Silencing Transcription Factor (REST) to its consensus RE1 motif, allowed deposition of enhancer-specific histone H3 lysine4 (K4) mono-methylation and histone H3K27 acetylation marks to activate an enhancer-promoter interaction. Restoration of REST binding or BET-domain inhibition resulted in a significant reduction in the enhancer marks and enhancer-promoter interaction and involved histone H3K27me3 deposition at the REST binding site, to facilitate gene silencing and sensitization of ATRTs to NK-mediated cytolysis. Thus, our study has identified a novel function for REST as a modulator of tumor-intrinsic enhancer activity and tumor-extrinsic immune microenvironment. Of equal significance, we highlight a role of REST in recruiting the polycomb repressive complex-2 (PRC2) in gene silencing in ATRTs.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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