Modelling stromal FAK regulation of tumour growth, angiogenesis and progression

Abstract

The growth of tumours within a whole organism depends on the tumour microenvironment. This involves both resident stromal cells, such as endothelial cells and fibroblasts, and also bone marrow derived stromal cells. Integrins and growth factor receptors are known regulators of the tumour stroma. Since focal adhesion kinase (FAK) is a downstream effector of both integrins and growth factor receptors it likely also plays an important role in the regulation of the tumour microenvironment. Using adult mice where FAK is deleted ubiquitously after treatment with tamoxifen my data demonstrate that loss of stromal FAK inhibits tumour growth and angiogenesis but increases metastasis burden in experimental metastasis assays even when the tumour cells themselves still express FAK. Moreover, my data indicate loss of FAK in the bone marrow (BM) compartment and specifically in myeloid cells is sufficient to enhance tumour metastasis in experimental metastasis assays and in a spontaneous tumour model. In contrast loss of bone marrow FAK was not sufficient to affect primary tumour growth or angiogenesis. Taken together these data demonstrate that bone marrow derived FAK plays a significant but differential role in primary tumour growth and metastasis. 4 In a parallel study, I have developed a novel set of transgenic mice to enable us to dissect the mechanism of FAK function in primary tumour growth, metastasis and angiogenesis. I have generated point-mutant FAK knockin-knockout mice where mutant FAK is inducibly expressed (knockin) and endogenous FAK deleted (knockout) in specific cell types in adult mice. Here I show efficient deletion of mouse FAK and expression of FAK 861F mutant in tamoxifen-treated endothelial cells isolated from mice. Importantly the FAK 861F mutation in endothelial cells was sufficient to decrease tumour growth and angiogenesis in vivo suggesting that the FAK-P-Y861 phosphorylation site plays an important role in tumour growth and angiogenesis.