Although an in vitro 3D environment cannot completely mimic the in vivo tumor site, embedding tumor cells in a 3D extracellular matrix (ECM) allows for the study of cancer cell behaviors and the screening of anti-metastatic reagents with a more in vivo-like context. Here we explored the behaviors of MDA-MB-231 breast cancer cells embedded in 3D collagen I. Diverse tumor environmental conditions (including cell density, extracellular acidity, or hypoxia as mimics for a continuous tumor growth) reduced JNKs, enhanced TGFβ1/Smad signaling activity, induced Snail1, and reduced cortactin expression. The reduced JNKs activity blocked efficient formation of invadopodia labeled with actin, cortactin, or MT1-MMP. JNKs inactivation activated Smad2 and Smad4, which were required for Snail1 expression. Snail1 then repressed cortactin expression, causing reduced invadopodia formation and prominent localization of MT1-MMP at perinuclear regions. MDA-MB-231 cells thus exhibited less efficient collagen I degradation and invasion in 3D collagen I upon JNKs inhibition. These observations support a signaling network among JNKs, Smads, Snail1, and cortactin to regulate the invasion of MDA-MB-231 cells embedded in 3D collagen I, which may be targeted during screening of anti-invasion reagents.
|Number of pages
|Biochimica et Biophysica Acta - Molecular Cell Research
|Published - 2014 Sept
Bibliographical noteFunding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant for the Tumor Microenvironment Global Core Research Center (GCRC) funded by the Korean government (Ministry of Science, ICT & Future Planning) ( 2011-0030001 ), for senior researchers program (Leap research, 2012-0005606 / 2013-035235 ), and for Medicinal Bioconvergence Research Center ( NRF-2012M3A6A4054271 ) to JWL.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology