Integrins Can Act as Suppressors of Ras-Mediated Oncogenesis in the Drosophila Wing Disc Epithelium

SIMPLE SUMMARY: Studies over the last few years have revealed that integrin function in cancer is controversial. Accumulating evidence has shown that integrins can act as both tumour promoters or tumour suppressors. The targeting of integrins has shown enormous potential in both the diagnosis and treatment of cancer. Thus, further mechanistic insights into the roles of integrins as regulators of cancer progression are required. In this work, we aim to use the Drosophila model to gain insight into the role of these extracellular matrix receptors in tumoural progression. We find that the role of integrins as tumour suppressors is conserved. The depletion of integrins enhances the growth and invasive behaviour of tumours induced by a gain of function of an oncogenic form of Ras, by regulating cell shape and cycle progression. Furthermore, our results show that integrin loss enhances the ability of Ras tumour cells to affect the tumour microenvironment through the activation of the JNK pathway. ABSTRACT: Cancer is the second leading cause of death worldwide. Key to cancer initiation and progression is the crosstalk between cancer cells and their microenvironment. The extracellular matrix (ECM) is a major component of the tumour microenvironment and integrins, main cell-ECM adhesion receptors, are involved in every step of cancer progression. However, accumulating evidence has shown that integrins can act as tumour promoters but also as tumour suppressor factors, revealing that the biological roles of integrins in cancer are complex. This incites a better understating of integrin function in cancer progression. To achieve this goal, simple model organisms, such as Drosophila, offer great potential to unravel underlying conceptual principles. Here, we find that in the Drosophila wing disc epithelium the βPS integrins act as suppressors of tumours induced by a gain of function of the oncogenic form of Ras, Ras(V)(12). We show that βPS integrin depletion enhances the growth, delamination and invasive behaviour of Ras(V)(12) tumour cells, as well as their ability to affect the tumour microenvironment. These results strongly suggest that integrin function as tumour suppressors might be evolutionarily conserved. Drosophila can be used to understand the complex tumour modulating activities conferred by integrins, thus facilitating drug development.