A crosstalk between tumor cells and adipocytes facilitates tumor cell migration and invasion

Cancer cell invasion is modulated by their interaction with the tumor microenvironment (TME). In this article we have analyzed the cooperation of one of the TME cellular components, adipocytes, and breast tumor cells. Co-culture of these two types of cells increase tumor cell invasion and migration. This effect is associated to the de-differentiation of adipocytes that lose lipids and experience a transition to a mesenchymal phenotype. Furthermore, tumor cells are activated by adipocytes and undergo a partial epithelial-to-mesenchymal transition (EMT), which is characterized by a slow upregulation of Snail1. While partial EMT and increased migration both require fatty acid internalization, the adipocyte effect in our system does not rely on direct fatty acid transfer; instead, the tumor cells take these compounds directly from the culture medium. Moreover, adipocytes stimulate tumor cell metabolism by increasing glucose consumption and the production of reactive oxygen species (ROS); this metabolic shift is associated with the upregulated expression of NADPH oxidases (NOX) 1 and 5. Accordingly, a NOX inhibitor or NOX1 down-regulation prevents adipocyte-enhanced ROS generation, Snail1 expression and tumor cell migration. These results show that a bidirectional crosstalk between the two types of cells drives adipocyte dedifferentiation and tumor cell migration and invasion.