IMIM - Institut Hospital del Mar d'Investigacions Mèdiques

Epithelial-Mesenchymal Transition and Tumor Progression Antonio García de Herreros

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Molecular mechanisms promoting a pro-metastatic tumor stroma. Dr. Josep Baulida.

When epithelial cells from soft organs -such as breast, lung or intestine- degenerate forming a tumor, the surrounding connective tissue reacts as in wounds. Thus, a desmoplasic response characterized a fibrillar network around the tumor is often initiated by unique signals released by tumor cells, such as releasing TGFb. An emerging research field to explain the acquisition of tumor malignance (when tumors become invasive and metastatic) is the study of the influence of the physical properties of the microenvironment on tumor cell behavior. Desmoplastic reactions modulate the mechanics of the tumor milieu by increases rigidity and tridimensional organization of the fiber, what is postulate to promote the invasive behavior of tumor cells.

Our research has shown that a transcription factor, Snail1, promotes the expression of mesenchymal genes in response to TGFb in both epithelial cells and fibroblasts as those in the stroma. The mechanism requires RELA (p65) subunit of the nuclear factor-kB (NF-kB), which binds and recruits PARP1 and Snail1to promoters of genes encoding extracellular matrix molecules, such as Fibronectin. The characterization of the molecular elements involved in the exchange of Snail1 from a repressor to a transcription activation protein complex and its physiological relevance is one of the focuses of our research.

We have demonstrated that cancer associated fibroblasts regulate the composition and physical properties of the extracellular matrix in a Snail1-dependent manner and that these properties promote malignant behavior of tumor cells. In a study involving 370 invasive breast carcinomas, we found that Snail1 expression in stromal fibroblasts is an indicator of poor prognosis. We also found expression of Snail1 in fibroblasts associated skin wounds, which has proved to be essential for correct closure of the wound. We are currently extending our study to other types of tumors, dissecting the mechanisms that drive the organization of the desmoplastic tumor stroma and studying how interfere with the molecular mechanisms we have characterized in order to describe molecules with therapeutic potential.

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