title: E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade.
abstract: Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is a common event and is associated with disease aggressiveness and poor prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focussed on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecad-dependent invasion. To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis; nonetheless, at the invasive front, cells ectopically expressed Laminin A and βPS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin γ2 (LM-γ2), β1 and β4 integrin, when compared with Ecad-competent ones. We showed that LM-γ2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM-γ2. This is the ﬁrst evidence that ectopic Laminin expression depends on Ecad loss and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-γ2 signalling regulators as molecular targets to impair gastric cancer progression.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Andalusian Centre for Developmental Biology (CABD), Seville, Spain, Instituto de Engenharia Biomédica (INEB), Instituto de Investigação e Inovação em Saúde (i3S).
authors.forename: Joana
authors.initials: J
authors.lastname: Caldeira
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S).
authors.forename: Joana
authors.initials: J
authors.lastname: Figueiredo
authors.affiliation: Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Brás-Pereira
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S).
authors.forename: Patrícia
authors.initials: P
authors.lastname: Carneiro
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S).
authors.forename: Ana M
authors.initials: AM
authors.lastname: Moreira
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S).
authors.forename: Marta T
authors.initials: MT
authors.lastname: Pinto
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
authors.forename: João B
authors.initials: JB
authors.lastname: Relvas
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S), Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal, Centro Hospitalar São João, Porto, Portugal and.
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: Instituto de Engenharia Biomédica (INEB), Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS), Porto, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Barbosa
authors.affiliation: Andalusian Centre for Developmental Biology (CABD), Seville, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Casares
authors.affiliation: Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal.
authors.forename: Florence
authors.initials: F
authors.lastname: Janody
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S), Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal, rseruca@ipatimup.pt.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D007797:Laminin / Q000235:genetics*; D009361:Neoplasm Invasiveness; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation
chemical_list: D015820:Cadherins; D029721:Drosophila Proteins; C400567:LAMC2 protein, human; D007797:Laminin; C084098:laminin A