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Biochim Biophys Acta. 2014 Sep;1843(9):2037-54. doi: 10.1016/j.bbamcr.2014.05.007. Epub 2014 May 24.

Snail1 induced in breast cancer cells in 3D collagen I gel environment suppresses cortactin and impairs effective invadopodia formation.

Author information

1
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Republic of Korea.
2
School of Mechanical and Aerospace Engineering, Seoul National University, Republic of Korea.
3
Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
4
Department of Pharmacology, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
5
Interdisciplinary Program in Genetic Engineering, Seoul National University, Republic of Korea.
6
Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
7
Department of Pharmacology, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
8
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Republic of Korea; Interdisciplinary Program in Genetic Engineering, Seoul National University, Republic of Korea. Electronic address: jwl@snu.ac.kr.

Abstract

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.

KEYWORDS:

3D collagen; Cortactin; Invasion; JNK; Snail1

PMID:
24861866
DOI:
10.1016/j.bbamcr.2014.05.007
[Indexed for MEDLINE]
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