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 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.

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 wt and mutants of the E- and P-cadherin, series of primary tumors, and several in vitro and in vivo experimental models (CAM, Drosophila, and nude mice).

The group is structured in three working teams headed by the 3 core CVs. SERUCA’s team (group coordinator) aims at identifying the key molecules and signaling networks mediated by E-cadherin mutants in cancer, namely gastric cancer. PAREDES’s working team will concentrate on the relevant role of the adhesion molecule P-cadherin in cancer. FIGUEIREDO’s working team will dissect the molecular mechanisms and functional consequences 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.

PAST RESEARCH

SERUCA’s team is the worldwide expert of functional assays of germline mutations of E-cadherin associated to hereditary diffuse gastric cancer. Using stable cell lines carrying CDH1 germline missense mutations we identified the underlying signaling pathways associated to cancer cell motility and survival (EGFR and Notch1).  Moreover, we verified that E-cadherin is regulated by mechanisms of Endoplasmic Reticulum Quality Control. Using Drosophila we identified genes interacting with mutant human E-cadherin.

PAREDES´s team found that the adhesion molecule P-cadherin is overexpressed in 30% of breast carcinomas, being associated to cancer invasion and poor patient prognosis. Further, it was demonstrated that P-cadherin confers cancer stem cell properties to breast cancer cells, surviving in anchorage independent conditions and resisting to standard cancer therapies.

FIGUEIREDO’S team has shown that particular H. pylori genotypes increase the levels of gastric inflammation and epithelial damage, and the risk for gastric atrophy and cancer. Regarding interactions between H. pylori and the host gastric epithelial cells, the team has 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.

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.