title: Snail1 induced in breast cancer cells in 3D collagen I gel environment suppresses cortactin and impairs effective invadopodia formation.
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.
authors.affiliation: 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.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.affiliation: School of Mechanical and Aerospace Engineering, Seoul National University, Republic of Korea.
authors.forename: Sudong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Baek Gil
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Cheolhee
authors.initials: C
authors.lastname: Won
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Republic of Korea.
authors.forename: Seo Hee
authors.initials: SH
authors.lastname: Nam
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Suki
authors.initials: S
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Jihye
authors.initials: J
authors.lastname: Ryu
authors.affiliation: 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.
authors.forename: Haeng Eun
authors.initials: HE
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Doohyung
authors.initials: D
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.affiliation: School of Mechanical and Aerospace Engineering, Seoul National University, Republic of Korea.
authors.forename: Noo Li
authors.initials: NL
authors.lastname: Jeon
authors.affiliation: 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.
authors.forename: Tai Young
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Cho
authors.affiliation: 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.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002417:Cattle; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D024042:Collagen Type I / Q000494:pharmacology*; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005782:Gels; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000199:Actins; C495868:CTTN protein, human; D024042:Collagen Type I; D051356:Cortactin; D005782:Gels; D016755:Proto-Oncogene Proteins c-jun; C000604407:SNAI1 protein, human; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D010768:Phosphoserine; D048031:JNK Mitogen-Activated Protein Kinases; D053511:Matrix Metalloproteinase 14
keywords: 3D collagen; Cortactin; Invasion; JNK; Snail1