Matrix stiffness regulates tumor cell intravasation through expression and ESRP1-mediated alternative splicing of MENA
Wenjun Wang,
Paul V. Taufalele,
Martial Millet,
Kevin Homsy,
Kyra Smart,
Emily D. Berestesky,
Curtis T. Schunk,
Matthew M. Rowe,
Francois Bordeleau,
Cynthia A. Reinhart-King
Affiliations
Wenjun Wang
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
Paul V. Taufalele
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
Martial Millet
CHU de Québec-Université Laval Research Center (Oncology Division), Québec, QC G1R 3S3, Canada; CHU de Québec-Université Laval Research Center (Oncology Division), Québec, QC G1R 3S3, Canada
Kevin Homsy
CHU de Québec-Université Laval Research Center (Oncology Division), Québec, QC G1R 3S3, Canada; CHU de Québec-Université Laval Research Center (Oncology Division), Québec, QC G1R 3S3, Canada
Kyra Smart
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
Emily D. Berestesky
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
Curtis T. Schunk
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
Matthew M. Rowe
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
Francois Bordeleau
CHU de Québec-Université Laval Research Center (Oncology Division), Québec, QC G1R 3S3, Canada; CHU de Québec-Université Laval Research Center (Oncology Division), Québec, QC G1R 3S3, Canada; Département de biologie moléculaire, de biochimie médicale et de pathologie, Université Laval, Québec, QC G1V 0A6, Canada; Corresponding author
Cynthia A. Reinhart-King
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; Corresponding author
Summary: During intravasation, cancer cells cross the endothelial barrier and enter the circulation. Extracellular matrix stiffening has been correlated with tumor metastatic potential; however, little is known about the effects of matrix stiffness on intravasation. Here, we utilize in vitro systems, a mouse model, specimens from patients with breast cancer, and RNA expression profiles from The Cancer Genome Atlas Program (TCGA) to investigate the molecular mechanism by which matrix stiffening promotes tumor cell intravasation. Our data show that heightened matrix stiffness increases MENA expression, which promotes contractility and intravasation through focal adhesion kinase activity. Further, matrix stiffening decreases epithelial splicing regulatory protein 1 (ESRP1) expression, which triggers alternative splicing of MENA, decreases the expression of MENA11a, and enhances contractility and intravasation. Altogether, our data indicate that matrix stiffness regulates tumor cell intravasation through enhanced expression and ESRP1-mediated alternative splicing of MENA, providing a mechanism by which matrix stiffness regulates tumor cell intravasation.
