title: A membrane-type-1 matrix metalloproteinase (MT1-MMP)-discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells.
abstract: During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and pro-apoptotic properties. To develop metastatic capabilities, tumour cells must acquire the capacity to cope with this novel microenvironment. How cells interact with and respond to their microenvironment during cancer dissemination remains poorly understood. To address the impact of type I collagen on the fate of tumour cells, human breast carcinoma MCF-7 cells were cultured within three-dimensional type I collagen gels (3D COL1). Using this experimental model, we have previously demonstrated that membrane type-1 matrix metalloproteinase (MT1-MMP), a proteinase overexpressed in many aggressive tumours, promotes tumour progression by circumventing the collagen-induced up-regulation of BIK, a pro-apoptotic tumour suppressor, and hence apoptosis. Here we performed a transcriptomic analysis to decipher the molecular mechanisms regulating 3D COL1-induced apoptosis in human breast cancer cells. Control and MT1-MMP expressing MCF-7 cells were cultured on two-dimensional plastic plates or within 3D COL1 and a global transcriptional time-course analysis was performed. Shifting the cells from plastic plates to 3D COL1 activated a complex reprogramming of genes implicated in various biological processes. Bioinformatic analysis revealed a 3D COL1-mediated alteration of key cellular functions including apoptosis, cell proliferation, RNA processing and cytoskeleton remodelling. By using a panel of pharmacological inhibitors, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase specifically activated by collagen, as the initiator of 3D COL1-induced apoptosis. Our data support the concept that MT1-MMP contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering a drastic remodelling of the transcriptome of MCF-7 cells.
authors.affiliation: Laboratory of Tumour and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué (GIGA), Unit of Cancer, University of Liège, Liège, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Assent
authors.affiliation: Laboratory of Tumour and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué (GIGA), Unit of Cancer, University of Liège, Liège, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourgot
authors.affiliation: GIGA-Genomics platform, University of Liège, Liège, Belgium.
authors.forename: Benoît
authors.initials: B
authors.lastname: Hennuy
authors.affiliation: Systems and Modelling, Department of Electrical Engineering and Computer Science & GIGA-R, University of Liège, Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Geurts
authors.affiliation: Laboratory of Tumour and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué (GIGA), Unit of Cancer, University of Liège, Liège, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
authors.affiliation: Laboratory of Tumour and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué (GIGA), Unit of Cancer, University of Liège, Liège, Belgium.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.affiliation: Laboratory of Tumour and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué (GIGA), Unit of Cancer, University of Liège, Liège, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Maquoi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000737:chemistry / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D024042:Collagen Type I; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14