RAS interaction with P13K p110α is required for tumor-induced angiogenesis

Direct interaction of RAS with the P13K p110 alpha subunit mediates RAS-driven tumor development: however, it is not clear how p110 alpha/RAS-dependant signaling mediates interactions between tumors and host tissues. Here, using a murine tumor cell transfer model, we demonstrated that disruption of the interaction between RAS and p110 alpha within host tissue reduced tumor growth and tumor-induced angiogenesis, leading to improved survival of tumor-bearing mice, even when this interaction was intact in the transferred tumor. Furthermore, functional interaction of RAS with p110 alpha in host tissue was required for efficient establishment and growth of metastatic tumors. Inhibition of RAS and p110 alpha interaction prevented proper VEGF-A and FGF-2 signaling, which are required for efficient angiogenesis. Additionally, disruption of the RAS and p110 alpha interaction altered the nature of tumor-associated macrophages, inducing expression of markers typical for macrophage populations with reduced tumor-promoting capacity. Together, these results indicate that a functional RAS interaction with P13K p110 alpha, in host tissue is required for the establishment of a growth-permissive environment for the tumor, particularly for tumor-induced angiogenesis. Targeting the interaction of RAS with P13K has the potential to impair tumor formation by altering the tumorhost relationship, in addition to previously described tumor cell-autonomous effects.