LOXL2 and LOXL3: New players in tumourigenesis and metastasis
Ponente: Amparo Cano
Instituto de Investigaciones Biomedicas "Alberto Sols" (CSIC-UAM) [Madrid, Spain]
Host: Pedro Lazo
Fecha: 27/04/2017 - 27/04/2017
Salón de Actos del CIC
Lysyl oxidase-like 2 and -3 (LOXL2, LOXL3) are members of the lysyl oxidase protein family, primarily known for their role as extracellular enzymes; upon secretion they promote the stabilization of collagen and elastin fibers contributing to extracellular matrix (ECM) maturation. Beyond ECM cross-linking, lysyl oxidases have been involved in multiple biological functions including gene transcription, epithelial to mesenchymal transition (EMT), development, differentiation and angiogenesis, as well as in distinct pathologies such as fibrosis and cancer. Extensive work by our lab and others has established the deregulation of lysyl oxidases in cancer and their status has been associated with patient outcome in specific neoplasias. In particular, we described intracellular LOXL2 as a prognostic marker in larynx squamous cell carcinomas (SCC) and its association to distant metastasis in basal breast carcinomas. The mechanisms of LOXL2 involvement in tumour progression and metastasis are being uncovered using genetically modified mouse models (constitutive and conditional Knock-out as well as Knock-in lines for Loxl2) in the context of skin SCC and breast cancer.
Regarding LOXL3, its reported roles are essentially associated with LOXL3 extracellular activity regarding ECM maturation whereas LOXL3 involvement in cancer remains limited. Our recent studies show that LOXL3 expression is upregulated in melanoma tumours. Loss and gain of function approaches in multiple human melanoma cell lines have shed light on LOXL3 involvement in melanoma and the consequences of LOXL3 deregulation in primary and metastatic melanoma cells. Interestingly, melanoma cells are addicted to LOXL3 as its depletion halts cell proliferation and triggers apoptosis. Mechanistically, we have characterized that LOXL3 binds to proteins that maintain genome integrity (BRCA2, MSH2, SMC1A, NUMA1) and that LOXL3 absence promotes a defective DNA damage checkpoint activation, deficient DNA repair and aberrant mitosis in melanoma cells. These data uncover an unprecedented role for LOXL3 in melanoma biology and support the relevance of LOXL3 as a novel druggable target.