BioProject

Loss of normal tissue architecture is a hallmark of oncogenic transformation. More...

Loss of normal tissue architecture is a hallmark of oncogenic transformation. Mechanical forces sculpt tissue architectures during morphogenesis. However, their origins and consequences during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas (BCCs) form ‘buds’, while invasive squamous cell carcinomas (SCC) initiate as ‘folds’. Using computational modeling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumor architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer epithelia. In stratified epidermis, softening and enhanced remodeling of the basement membrane (BM) promote tumor budding, while BM stiffening promotes folding. We show that additional key forces stem from progenitor cell stratification and differentiation Tumor-specific suprabasal stiffness gradients are generated as oncogenic lesions progress toward malignancy, which we computationally predict alter extensile tensions on the tumor BM. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing BM stiffness elevates BM tensions in silico and potentiates invasive SCC progression in vivo. Our findings suggest that mechanical forces, exerted from above and below progenitors of multilayered epithelia, are integrally linked and function to shape premalignant tumor architectures and influence tumor progression. Overall design: Epidermal basal cells were FACS-purified from mouse embyros for RNA-seq analysis. Less...