A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.

Autor:	Simi AK; Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey., Anlaş AA; Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey., Stallings-Mann M; Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida., Zhang S; Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey., Hsia T; Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey., Cichon M; Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida., Radisky DC; Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida., Nelson CM; Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey. celesten@princeton.edu.; Department of Molecular Biology, Princeton University, Princeton, New Jersey.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 May 01; Vol. 78 (9), pp. 2277-2289. Date of Electronic Publication: 2018 Feb 26.
DOI:	10.1158/0008-5472.CAN-17-2899
Abstrakt:	Multinucleation 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 metalloproteinase-3 (MMP3) or TGFβ, known inducers of epithelial-mesenchymal 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. Cancer Res; 78(9); 2277-89. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu