PMID- 29483094
OWN - NLM
STAT- MEDLINE
DCOM- 20190521
LR  - 20190521
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 78
IP  - 9
DP  - 2018 May 1
TI  - A Soft Microenvironment Protects from Failure of Midbody Abscission and 
      Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.
PG  - 2277-2289
LID - 10.1158/0008-5472.CAN-17-2899 [doi]
AB  - 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 TGFbeta, 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. (c)2018 AACR.
CI  - (c)2018 American Association for Cancer Research.
FAU - Simi, Allison K
AU  - Simi AK
AD  - Department of Chemical and Biological Engineering, Princeton University, 
      Princeton, New Jersey.
FAU - Anlas, Alisya A
AU  - Anlas AA
AD  - Department of Chemical and Biological Engineering, Princeton University, 
      Princeton, New Jersey.
FAU - Stallings-Mann, Melody
AU  - Stallings-Mann M
AD  - Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida.
FAU - Zhang, Sherry
AU  - Zhang S
AD  - Department of Chemical and Biological Engineering, Princeton University, 
      Princeton, New Jersey.
FAU - Hsia, Tiffaney
AU  - Hsia T
AD  - Department of Chemical and Biological Engineering, Princeton University, 
      Princeton, New Jersey.
FAU - Cichon, Magdalena
AU  - Cichon M
AD  - Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida.
FAU - Radisky, Derek C
AU  - Radisky DC
AD  - Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida.
FAU - Nelson, Celeste M
AU  - Nelson CM
AD  - Department of Chemical and Biological Engineering, Princeton University, 
      Princeton, New Jersey. celesten@princeton.edu.
AD  - Department of Molecular Biology, Princeton University, Princeton, New Jersey.
LA  - eng
GR  - R21 HL110335/HL/NHLBI NIH HHS/United States
GR  - R01 CA187692/CA/NCI NIH HHS/United States
GR  - R21 HL118532/HL/NHLBI NIH HHS/United States
GR  - R01 GM083997/GM/NIGMS NIH HHS/United States
GR  - R01 HL120142/HL/NHLBI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180226
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Snail Family Transcription Factors)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Animals
MH  - Biomarkers, Tumor
MH  - Breast Neoplasms/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - *Epithelial-Mesenchymal Transition
MH  - Genomic Instability
MH  - Humans
MH  - Matrix Metalloproteinase 3/metabolism
MH  - Mechanotransduction, Cellular
MH  - Mice
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
MH  - Snail Family Transcription Factors/*metabolism
MH  - *Tumor Microenvironment
PMC - PMC5932229
MID - NIHMS946857
COIS- Conflict of interest statement: The authors declare no potential conflicts of 
      interest.
EDAT- 2018/02/28 06:00
MHDA- 2019/05/22 06:00
PMCR- 2019/05/01
CRDT- 2018/02/28 06:00
PHST- 2017/09/24 00:00 [received]
PHST- 2018/02/08 00:00 [revised]
PHST- 2018/02/20 00:00 [accepted]
PHST- 2018/02/28 06:00 [pubmed]
PHST- 2019/05/22 06:00 [medline]
PHST- 2018/02/28 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - 0008-5472.CAN-17-2899 [pii]
AID - 10.1158/0008-5472.CAN-17-2899 [doi]
PST - ppublish
SO  - Cancer Res. 2018 May 1;78(9):2277-2289. doi: 10.1158/0008-5472.CAN-17-2899. Epub 
      2018 Feb 26.