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A soft microenvironment protects from failure of Midbody abscission and multinucleation downstream of the EMT-promoting transcription factor snail

Author(s): Simi, Allison K.; Anlaş, Alişya A.; Stallings-Mann, Melody; Zhang, Sherry; Hsia, Tiffaney; et al

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dc.contributor.authorSimi, Allison K.-
dc.contributor.authorAnlaş, Alişya A.-
dc.contributor.authorStallings-Mann, Melody-
dc.contributor.authorZhang, Sherry-
dc.contributor.authorHsia, Tiffaney-
dc.contributor.authorCichon, Magdalena-
dc.contributor.authorRadisky, Derek C.-
dc.contributor.authorNelson, Celeste M.-
dc.date.accessioned2020-01-31T21:58:20Z-
dc.date.available2020-01-31T21:58:20Z-
dc.date.issued2018-05-01en_US
dc.identifier.citationSimi, AK, Anlaş, AA, Stallings-Mann, M, Zhang, S, Hsia, T, Cichon, M, Radisky, DC, Nelson, CM. (2018). A soft microenvironment protects from failure of Midbody abscission and multinucleation downstream of the EMT-promoting transcription factor snail. Cancer Research, 78 (2277 - 2289). doi:10.1158/0008-5472.CAN-17-2899en_US
dc.identifier.urihttp://arks.princeton.edu/ark:/88435/pr1hn3b-
dc.description.abstractMultinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloprotei-nase-3 (MMP3) or TGFb, known inducers of epithelial–mes-enchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Significance: These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.en_US
dc.format.extent2277 - 2289en_US
dc.language.isoen_USen_US
dc.relation.ispartofCancer Researchen_US
dc.rightsAuthor's manuscripten_US
dc.titleA soft microenvironment protects from failure of Midbody abscission and multinucleation downstream of the EMT-promoting transcription factor snailen_US
dc.typeJournal Articleen_US
dc.identifier.doidoi:10.1158/0008-5472.CAN-17-2899-
pu.type.symplectichttp://www.symplectic.co.uk/publications/atom-terms/1.0/journal-articleen_US

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