Epithelial Interactions in Cancer

ABOUT

The long-term goal of the EPIC (EPithelial Interactions in Cancer) 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 aims to establish the contribution of adhesion molecules (E- and P-cadherins), infections (Helicobacter pylori and the microbiota), and non-neoplastic components of the tumour tissue (fibroblast-like cells, the cancer cell secreted peptides and the elements of the extracellular matrix), to cancer development.

EPIC researchers have expertise in adhesion cancer-associated molecules and in host-H. pylori interactions, and complementary skills on genetics, molecular and cell biology, microbiology, pathology, and oncology. The group has available biological reagents that include stable cell lines expressing wild-type and mutants of the E- and P-cadherin, series of primary tumours, and several in vitro and in vivo experimental models (CAM, Drosophila, and nude mice).

The group is structured in three working teams, each headed by a core CV. SERUCA’s team (group coordinator) aims at identifying the key molecules and signalling networks mediated by E-cadherin mutants in cancer, namely gastric cancer. PAREDES’s team concentrates on the relevant role of the adhesion molecule P-cadherin in cancer. FIGUEIREDO’s team aims at dissecting the molecular mechanisms underlying H. pylori-mediated gastric cancer.

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.

 

RESEARCH

SERUCA’S team has been focused on the functional consequences of CDH1missense variants in the context of hereditary cancer and congenital malformations. In that regard, our Lab is now considered a worldwide reference centre to evaluate E-cadherin pathogenicity. Using a unique panel of about 70 E-cadherin missense mutations spread along the gene and associated to disease (hereditary diffuse gastric cancer, lobular breast cancer and congenital malformations), we determined cellular and tissue effects mediated by E-cadherin dysfunction. In particular, we explore cell structural properties, cell morphology, cell-cell and cell-matrix adhesion, migration and invasion abilities. Two bioimaging tools were also developed for a detailed quantitative analysis of protein expression and cell topological features, taking into account intercellular heterogeneity. Of note, we identified distinct trafficking partners and novel mechanisms that hamper E-cadherin translation, folding and deliver to the basolateral membrane, which constitute the molecular basis for hereditary cancer.

Currently, we aim to identify critical moieties and signalling pathways that are responsible for the clinical spectrum and pleiotropic nature of CDH1germline mutations. We propose that the E-cadherin-ECM-integrin crosstalk may play a role in this process.

 

PAREDES’ team has been focused on understanding the functional consequences of P-cadherin overexpression in triple negative basal-like breast cancer. In the past 5 years, we have demonstrated that the expression of this adhesion molecule is significantly associated with poor patients’ survival when evaluated in the primary tumour, but also in lymph node metastases, which information can be highly valuable for clinical therapeutic decisions. Mechanistically, we revealed that P-cadherin induces tumorigenesis and cell invasion through cell-cell adhesion disruption and through the strength induced on cell-matrix adhesion. Also novel, we revealed that P-cadherin expression associates with cancer cell populations with stem cell properties and a glycolytic metabolism plus an acid-resistant phenotype. We are now interested in uncover how P-cadherin overexpression affects the actin cytoskeleton, centriole amplification and chromosome missegregation and how molecular features can reprogram stem cell properties in P-cadherin breast cancer cells.

 

FIGUEIREDO’S team has shown that particular H. pylori virulence-associated genotypes increase the levels of gastric inflammation and epithelial damage, and the risk for gastric atrophy and cancer. Recently, we showed that promoter heterogeneity in the gene encoding the H. pylori CagA oncoprotein influences gastric epithelial inflammation and disease risk. Regarding interactions between H. pylori and the host gastric cells, we showed shown that H. pylori alters cell-cell adhesion and increases cell invasion by upregulating the expression and activity of multiple matrix metalloproteases. In particular, H. pylori strains containing CagA activate EGFR, Src and ERK1/2, to modulate MMP10 expression and secretion, which may ultimately result in gastric epithelial damage and potentiate transformation. We are currently interested in the gastric microbiome and in determining its contribution to gastric carcinogenesis.

Targeted knockdown of Drosophila Epithelial-cadherin (green), in the posterior compartment of the wing imaginal disc, results in invasion of wiltype tissues, ectopic Laminin expression (red) and MMP upregulation (blue). This is only observed at the interface with Drosophila Epithelial-cadherin expressing cells.