期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 27, 页码 8314-8319出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1505421112
关键词
alternative splicing; extracellular matrix; matrix stiffness; angiogenesis; cancer progression
资金
- National Institutes of Health (NIH) [1R01HL127499]
- National Science Foundation (NSF) [1055502, 1435755]
- NIH [R01 CA163255, T32 GM008500]
- NSF Graduate Science, Technology, Engineering and Mathematics (STEM) fellowship
- Morgan Family fellowship
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1055502] Funding Source: National Science Foundation
- Directorate For Engineering
- Div Of Civil, Mechanical, & Manufact Inn [1435755, 1233827] Funding Source: National Science Foundation
Alternative splicing of proteins gives rise to different isoforms that play a crucial role in regulating several cellular processes. Notably, splicing profiles are altered in several cancer types, and these profiles are believed to be involved in driving the oncogenic process. Although the importance of alternative splicing alterations occurring during cancer is increasingly appreciated, the underlying regulatory mechanisms remain poorly understood. In this study, we use both biochemical and physical tools coupled with engineered models, patient samples, and a murine model to investigate the role of the mechanical properties of the tumor microenvironment in regulating the production of the extra domain-B (EDB) splice variant of fibronectin (FN), a hallmark of tumor angiogenesis. Specifically, we show that the amount of EDB-FN produced by endothelial cells increases with matrix stiffness both in vitro and within mouse mammary tumors. Matrix stiffness regulates splicing through the activation of serine/arginine rich (SR) proteins, the splicing factors involved in the production of FN isoforms. Activation of the SR proteins by matrix stiffness and the subsequent production of EDB-FN are dependent on intracellular contractility and PI3K-AKT signaling. Notably, matrix stiffness-mediated splicing is not limited to EDB-FN, but also affects splicing in the production of PKC beta II and the VEGF 165b splice variant. Together, these results demonstrate that the mechanical properties of the microenvironment regulate alternative splicing and establish a previously unidentified mechanism by which cells can adapt to their microenvironment.
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