Research
Epithelial Interactions in Cancer

OVERVIEW

The long term goal of our Group is to uncover how epithelial cell-cell and cell-matrix junctions, as well as the surrounding microenvironment, can influence cancer progression. Specifically, and based on three common epithelial-derived cancers (gastric, breast, and colorectal), the group will establish the contribution of adhesion molecules (E- and P-cadherins), infections (Helicobacter pylori and the microbiota), and non-neoplastic components of the tumor tissue (fibroblast-like cells, the cancer cell secreted peptides and the elements of the extracellular matrix), to alter epithelial homeostasis and influence cancer development.

The accomplishment of these research goals will contribute to the development of new tools for cancer screening, prevention, and patient surveillance, as well as therapeutic strategies based on the modulation of cancer cell interactions.

 

SERUCA’s team has been involved in determining the role played by E-cadherin alterations in cancer, with a specific focus on hereditary diffuse gastric cancer (HDGC). We are the reference centre for studying the pathogenic value of all CDH1 germline missense mutations detected in HDGC worldwide (from New Zeeland, Europe, Asia to North and South America). We have established more than 40 patient derived CDH1 mutant stable cell lines, in order to assess their pathogenic role (using in silico, in vitro, and bioimaging tools). Using in vitro and in vivo models, we identified candidate genes and/or pathways interacting differentially with the wild-type and mutant (associated to HDGC) human E-cadherin. In clinical genetics, we described a new syndrome with HDGC and midline malformations associated with CDH1 germline mutations and determined the role of CDH1 mutations in cleft lip palate.

 

Selected Publications

  1. Figueiredo J, Söderberg O, Simões-Correia J, Grannas K, Suriano G, Seruca R. The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC. European Journal of Human Genetics 21:301-9, 2013.

    http://www.ncbi.nlm.nih.gov/pubmed/22850631

  2. Ferreira AC, Suriano G, Mendes N, Gomes B, Wen X, Carneiro F, Seruca R, Machado JC. E-cadherin impairment increases cell survival through Notch-dependent upregulation of Bcl-2. Human Molecular Genetics 21:334-43, 2012.

    http://www.ncbi.nlm.nih.gov/pubmed/21989054

  3. Caldeira J, Simões-Correia J, Paredes J, Pinto MT, Sousa S, Corso G, Marrelli D, Roviello F, Pereira PS, Weil D, Oliveira C, Casares F, Seruca R. CPEB1, a novel gene silenced in gastric cancer: a Drosophila approach. Gut 61:1115-23, 2012.

    http://www.ncbi.nlm.nih.gov/pubmed/22052064

  4. Frebourg T, Oliveira C, Hochain P, Karam R, Manouvrier S, Graziadio C, Vekemans M, Hartmann A, Baert-Desurmont S, Alexandre C, Lejeune Dumoulin S, Marroni C, Martin C, Castedo S, Lovett M, Winston J, Machado JC, Attié T, Jabs EW, Cai J, Pellerin P, Triboulet JP, Scotte M, Le Pessot F, Hedouin A, Carneiro F, Blayau M, Seruca R.  Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. Journal of Medical Genetics 43:138-42, 2006.

    http://www.ncbi.nlm.nih.gov/pubmed/15831593

  5. Suriano G, Oliveira C, Ferreira P, Machado JC, Bordin MC, De Wever O, Bruyneel EA, Moguilevsky N, Grehan N, Porter TR, Richards FM, Hruban RH, Roviello F, Huntsman D, Mareel M, Carneiro F, Caldas C, Seruca R. Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. Human Molecular Genetics 12:575-82, 2003.

    http://www.ncbi.nlm.nih.gov/pubmed/12588804

 

PAREDES’s team has demonstrated that P-cadherin, an adhesion molecule usually expressed in the myoepithelial/basal layer of the normal breast, is overexpressed in about 30% of in situ and invasive breast carcinomas (significantly in HER2+ and TNBC), being highly associated to tumor aggressiveness and worse patient disease-free and overall survival. We have found that P-cadherin is highly associated to loss of cell polarity in tumors and is able to promote motility/migration and invasion of breast cancer cells, by regulating the expression and activity of MMP1 and MMP2. Indeed, these MMPs give rise to a soluble form of P-cadherin that mediates pro-invasive capacity. Moreover, we demonstrated that P-cadherin confers stem cell properties to breast cancer cells, as well as resistance to radiotherapy. Recently, we have established that there is a crosstalk between P-cadherin and the laminin receptor α6β4 integrin signaling pathway. We have also found that P-cadherin interferes with the normal function of E-cadherin in breast cancer, inducing cytoplasmic catenins localization.

 

Selected Publications

  1. Vieira AF, Ribeiro AS, Dionísio MR, Sousa B, Nobre AR, Albergaria A, Santiago-Gómez A, Mendes N, Gerhard R, Schmitt F, Clarke RB, Paredes J. P-cadherin signals through the laminin receptor α6β4 integrin to induce stem cell and invasive properties in basal-like breast cancer cells. Oncotarget 2014.

    http://www.ncbi.nlm.nih.gov/pubmed/24553076

  2. Ribeiro AS, Sousa B, Carreto L, Mendes N, Nobre AR, Ricardo S, Albergaria A, Cameselle-Teijeiro JF, Gerhard R, Söderberg O, Seruca R, Santos MA, Schmitt F, Paredes J. P-cadherin functional role is dependent on E-cadherin cellular context: a proof of concept using the breast cancer model. Journal of Pathology 229:705-18, 2013.

    http://www.ncbi.nlm.nih.gov/pubmed/23180380

  3. Paredes J, Figueiredo J, Albergaria A, Oliveira P, Carvalho J, Ribeiro AS, Caldeira J, Costa AM, Simões-Correia J, Oliveira MJ, Pinheiro H, Pinho SS, Mateus R, Reis CA, Leite M, Fernandes MS, Schmitt F, Carneiro F, Figueiredo C, Oliveira C, Seruca R. Epithelial E- and P-cadherins: role and clinical significance in cancer. Biochimica Biophysica Acta - Reviews on Cancer 1826:297-311, 2012.

    http://www.ncbi.nlm.nih.gov/pubmed/22613680

  4. Vieira AF, Ricardo S, Ablett MP, Dionísio MR, Mendes N, Albergaria A, Farnie G, Gerhard R, Cameselle-Teijeiro JF, Seruca R, Schmitt F, Clarke RB, Paredes J. P-cadherin is coexpressed with CD44 and CD49f and mediates stem cell properties in basal-like breast cancer. Stem Cells 30: 854-64, 2012.

    http://www.ncbi.nlm.nih.gov/pubmed/22389315

  5. Ribeiro AS, Albergaria A, Sousa B, Correia AL, Bracke M, Seruca R, Schmitt FC, Paredes J. Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells. Oncogene 29:392-402, 2010.

    http://www.ncbi.nlm.nih.gov/pubmed/19901964

 

FIGUEIREDO’S team has shown that particular Helicobacter pylori vacA and cagA genotypes significantly increase the levels of gastric inflammation and epithelial damage, and the risk for gastric atrophy and gastric carcinoma. In relation to the interactions between H. pylori and the host gastric epithelial cells, we have shown that H. pylori targets E-cadherin and accentuates loss of cell-cell adhesion and increases cell invasion via c-Met activation and increased matrix metalloproteases activity. We have also demonstrated that H. pylori infection affects base excision and mismatch repair of gastric cells in vitro and in vivo and induces genomic instability in nuclear and mitochondrial DNA, putatively leading to a MSI phenotype, and thus contributing to gastric carcinogenesis in infected individuals.

 

Selected Publications

  1. Gonzalez CA, Figueiredo C, Bonet C, Ferreira RM, Pardo ML, Ruiz Liso JM, Alonso P, Sala N, Capella G, Sanz-Anquela JM. Helicobacter pylori cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: a long term follow up in a high-risk area in Spain. American Journal of Gastroenterology 106: 867-74, 2011.

    http://www.ncbi.nlm.nih.gov/pubmed/21285949

  2. Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, Capelinha AF, Quint W, Caldas C, van Doorn LJ, Carneiro F, Sobrinho-Simões M. Helicobacter pylori and interleukin-1 genotyping: An opportunity to identify high-risk individuals for gastric carcinoma. Journal of the National Cancer Institute 94: 1680-7, 2002.

    http://www.ncbi.nlm.nih.gov/pubmed/12441323

  3. Oliveira MJ, Costa AM, Costa AC, Ferreira RM, Sampaio P, Machado JC, Seruca R, Mareel M, Figueiredo C. CagA associates with c-Met, E-Cadherin, and p120-aatenin in a multiproteic complex that suppresses Helicobacter pylori-induced cell-invasive phenotype. Journal of Infectious Diseases 200: 745-55, 2009.

    http://www.ncbi.nlm.nih.gov/pubmed/19604117

  4. Oliveira MJ, Costa AC, Costa AM, Henriques L, Suriano G, Atherton JC, Machado JC, Carneiro F, Seruca R, Mareel M, Leroy A, Figueiredo C. Helicobacter pylori induces gastric epithelial cell invasion in a c-Met and type IV secretion system dependent manner. Journal of Biological Chemistry 281:34888-96, 2006.

    http://www.ncbi.nlm.nih.gov/pubmed/16990273

  5. Machado AM, Figueiredo C, Touati E, Máximo V, Sousa S, Michel V, Carneiro F, Nielsen FC, Seruca R, Rasmussen LJ. Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clinical Cancer Research 15:2995-3002, 2009.

    http://www.ncbi.nlm.nih.gov/pubmed/19383819

 

 
 
Send Email
From
To
Subject