Epithelial-Mesenchymal Transition and Metastasis

LOXL2 enzyme belongs to the family of lysyl oxidases, formed by lysyl oxidase (LOX) and four "lysyl oxidase-like" (LOXL1-LOXL4) paralogs. These enzymes are amino oxidases with a lysine-tyrosilquinone cofactor and catalyse the oxidative de-amination of ε-amino groups in peptidyl-lysine residues promoting covalent crosslinks. The accumulated evidence in the last decade shows the participation of lysyl oxidase members, especially LOX, LOXL2 and LOXL3, in a multitude of biological functions from remodelling the extracellular matrix (ECM) to tumorigenesis and metastasis depending on their location (intra or extracellular). Our previous studies showed that LOXL2 is a poor prognostic factor in human squamous cell carcinomas and is associated with metastatic dissemination of triple negative (basal) breast carcinomas. Intracellular LOXL2 regulates key metastasis-associated processes such as epithelial to mesenchymal transition (EMT), epidermal differentiation of premalignant skin lesions and the pre-metastatic niche formation. Mechanistically, these functions are carried out by LOXL2 through its interaction with EMT or differentiation related transcription factors (Snail1, E47 or Klf4) or by activation of the FAK / Src signalling pathway or the UPR (Unfolded protein response). In order to gain mechanistic insight regarding LOXL2 role in breast cancer, we uncovered the association of LOXL2 with various protein complexes with depicted functions in mRNA stability and alternative splicing. Actually, we are analysing the contribution of LOXL2 to mRNA stability and alternative splicing and its relevance to breast cancer and have started a search for inhibitors of LOXL2 action in tumour progression and metastasis.