BACR Translational Research Award: Exploring hypoxia-mediated tumour progression
Janine Erler
The Institute of Cancer Research, London, UK
Metastasis is responsible for over 90% of cancer patient deaths. The metastatic process is strongly influenced by the tumour micro-environment, including hypoxia (low oxygen) and increased matrix stiffness.
We have found that lysyl oxidase (LOX) and lysyl oxidase-like 2 (LOXL2) are hypoxia-induced enzymes that cross-link collagens and elastins in the extracellular matrix increasing matrix stiffness. LOX and LOXL2 are clinically associated with metastasis and poor patient survival. We have shown that inhibition of LOX prevents metastasis in several cancer models through effects on invasion, pre-metastatic niche formation and metastatic tumour growth (Erler et al, 2006, Nature; Erler et al, 2009, Cancer Cell; Brustugun et al, unpublished).
We have now characterised the role of LOXL2 in breast cancer metastasis (Barker et al, unpublished). Using a syngeneic model and transgenic mouse models of breast cancer, we show that LOXL2 is able to drive metastasis independent of LOX. We show that LOXL2 is needed for cell-matrix adhesion interactions necessary for tumour cell invasion and successful metastatic dissemination and tumour growth. We show effectiveness of a LOXL2 inhibitor on already formed metastases, suggesting it is a good therapeutic target for the treatment of metastatic breast cancer.
We are currently characterising the signalling networks associated with LOX and LOXL2 that drive metastasis, and further characterising the pre-metastatic niche.
