Epithelial Interactions in Cancer
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 namely cancer cell invasion, migration and metastasis. 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) and non-neoplastic components of the tumour tissue to cancer development.
EPIC researchers have expertise in adhesion and cancer-associated pathways involving host cellular and non-cellular interactions within the tumour tissue. The group encompasses complementary skills on molecular and cell biology, pathology, and oncology. Furthermore, it has available unique biological reagents that include stable cell lines expressing wild-type and mutants of the two major adhesion molecules (E- and P-cadherin), series of primary tumours and several in vitro and in vivo experimental models.
The group is structured in three working teams, each one headed by a core CV. SERUCA’s team (group coordinator) aims at identifying the key molecules and signalling networks mediated by E-cadherin dysfunction in cancer. PAREDES’s team concentrates on the relevance of the adhesion molecule P-cadherin in cancer. VELHO´s team aims at dissecting the role of oncogenic signalling in the interaction of cancer cells with the tumour microenvironment and how it impacts cancer tissue remodelling, and to develop new tools for patient treatment and disease monitoring.
The accomplishment of these research goals will contribute to the development of new tools for patient surveillance, but also to the design of novel therapeutic strategies based on the modulation of cancer cell interactions to stop cancer cell invasion and metastasis.
SERUCA’S team has been focused on the functional consequences of loss of function of E-cadherin in cancer cell invasion. Of note, we identified distinct trafficking-related partners and novel mechanisms that hamper E-cadherin translation, folding and deliver to the basolateral membrane that lead to loss of function of this adhesion molecule impairing cell adhesion and increased cell invasion. Currently, we aim to identify critical moieties and signalling pathways that are involved in disruption of epithelial architecture and consequent cell invasive behaviour. We verified that upon loss of E-cadherin, there is a remodelling of cell-ECM interactions, cytoskeletal reorganization and cell reshaping. However, how these modifications cooperate to confer an effective invasive capacity is not yet known. Therefore we aim to unravel how E-cadherin loss of function and consequent abnormal cell-matrix adhesion activate a specific mechanotransduction program leading to invasion and migration. Moreover, we are developing new methods to isolate CTCs based on knowledge yielded by this team concerning cancer cell matrix interactions. Using our knowledge on cell biology of adhesion molecules, we provide services worldwide on functional assays of E-cadherin missense mutations found within the frame of International Gastric Cancer Linkage Consortium.
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 remodelling of cell-matrix adhesion. Also novel, we revealed that P-cadherin expression associates with cancer cell populations with stem cell properties and a glycolytic metabolism concomitant with an acid-resistant phenotype. We are now interested in uncover how P-cadherin overexpression affects the actin cytoskeleton, centriole amplification and chromosome missegregation, and whether molecular features can reprogram stem cell properties in P-cadherin breast cancer cells.
VELHO’s team is focused on the role of oncogenic signalling on the orchestration of the crosstalk between colorectal cancer cells and the tumour microenvironment, and how it impacts tumour initiation and progression. By identifying the regulators of this crosstalk, we expect to uncover novel treatment strategies targeting the interaction of cancer cells with the microenvironment. Current work from our team supports a role for mutant KRAS in mediating cancer cell response to microenvironment factors either by regulating the response of cancer cells to external factors or by promoting a pro-tumorigenic microenvironment. In particular, we have found that, by regulating clinically relevant molecules involved in the communication with the microenvironment, KRAS mutant colorectal cancer cells are likely to impact cancer cell invasion, stemness, and immune escape when challenged with microenvironmental-derived factors. Additionally, by affecting the properties of cancer-associated fibroblasts, KRAS mutant colorectal cancer cells are likely to impact cancer tissue remodelling. Our team applies in vivo and in vitro studies such as genetically engineered mouse models, 2D and 3D cell culture systems, including patient- and mouse-derived organoids, to answer clinically relevant questions.
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