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

TitleA Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.
Publication TypeJournal Article
Year of Publication2018
AuthorsSimi, AK, Anlas, AA, Stallings-Mann, M, Zhang, S, Hsia, T, Cichon, M, Radisky, DC, Nelson, CM
JournalCancer Res
Volume78
Issue9
Pagination2277-2289
Date Published2018 05 01
ISSN1538-7445
KeywordsAnimals, Biomarkers, Tumor, Breast Neoplasms, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Genomic Instability, Humans, Matrix Metalloproteinase 3, Mechanotransduction, Cellular, Mice, Reactive Oxygen Species, Signal Transduction, Snail Family Transcription Factors, Tumor Microenvironment
Abstract

<p>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. These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. .</p>

DOI10.1158/0008-5472.CAN-17-2899
Alternate JournalCancer Res.
PubMed ID29483094
PubMed Central IDPMC5932229
Grant ListR21 HL110335 / HL / NHLBI NIH HHS / United States
R01 CA187692 / CA / NCI NIH HHS / United States
R21 HL118532 / HL / NHLBI NIH HHS / United States
R01 GM083997 / GM / NIGMS NIH HHS / United States
R01 HL120142 / HL / NHLBI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States