Mechanics of a multilayer epithelium instruct tumour architecture and function

• Type of Material: Article
• Authors: Vincent F. Fiore, Rockefeller University; Matej Krajnc, Princeton University; Felipe Garcia Quiroz, Emory University; John Levorse, Rockefeller University; H. Amalia Pasolli, Rockefeller University; Stanislav Y. Shvartsman, Princeton University; Elaine Fuchs, Rockefeller University
• Language: English
• Date: 2020-09-02
• Publisher: NATURE RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2020
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-020-2695-9
• Title of Journal or Parent Work: NATURE
• Volume: 585
• Issue: 7825
• Start Page: 433
• End Page: +
• Grant/Funding Information: V.F.F. was supported by the NIH–National Cancer Institute (NCI) Cancer Biology Training Program (grant CA009673-39) and a Charles H. Revson Senior Fellowship in Biomedical Sciences (Revson Foundation). M.K. was supported by the Slovenian Research Agency (research project Z1-1851). F.G.Q. holds a Career Award at the Scientific Interface from Burroughs Wellcome Fund. E.F. is a Howard Hughes Medical Institute (HHMI) Investigator. This research was supported by NIH grant R01-AR27883 to E.F.
• Keywords: HALLMARKS; MORPHOGENESIS; Science & Technology - Other Topics; COLLAGEN-IV; DYNAMICS; BASEMENT-MEMBRANE; Science & Technology; ACTOMYOSIN NETWORKS; STEM-CELLS; MORPHOLOGY; CELL MECHANICS; Multidisciplinary Sciences; DISSECTION
• Research Categories: Biology, Cell

Abstract

Loss of normal tissue architecture is a hallmark of oncogenic transformation1. In developing organisms, tissues architectures are sculpted by mechanical forces during morphogenesis2. However, the origins and consequences of tissue architecture during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas form ‘buds’, while invasive squamous cell carcinomas initiate as ‘folds’. Here, using computational modelling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumour architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer, epithelia. In stratified epidermis, meanwhile, softening and enhanced remodelling of the basement membrane promote tumour budding, while stiffening of the basement membrane promotes folding. Additional key forces stem from the stratification and differentiation of progenitor cells. Tumour-specific suprabasal stiffness gradients are generated as oncogenic lesions progress towards malignancy, which we computationally predict will alter extensile tensions on the tumour basement membrane. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing the stiffness of basement membranes increases membrane tensions in silico and potentiates the progression of invasive squamous cell carcinomas in vivo. Our findings suggest that mechanical forces—exerted from above and below progenitors of multilayered epithelia—function to shape premalignant tumour architectures and influence tumour progression.