title: RAS interaction with PI3K p110α is required for tumor-induced angiogenesis.
abstract: Direct interaction of RAS with the PI3K p110α subunit mediates RAS-driven tumor development: however, it is not clear how p110α/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 p110α 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 p110α in host tissue was required for efficient establishment and growth of metastatic tumors. Inhibition of RAS and p110α interaction prevented proper VEGF-A and FGF-2 signaling, which are required for efficient angiogenesis. Additionally, disruption of the RAS and p110α 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 PI3K p110α 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 PI3K has the potential to impair tumor formation by altering the tumor-host relationship, in addition to previously described tumor cell-autonomous effects.
authors.forename: Miguel Manuel
authors.initials: MM
authors.lastname: Murillo
authors.forename: Santiago
authors.initials: S
authors.lastname: Zelenay
authors.forename: Emma
authors.initials: E
authors.lastname: Nye
authors.forename: Esther
authors.initials: E
authors.lastname: Castellano
authors.forename: Francois
authors.initials: F
authors.lastname: Lassailly
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism* / Q000556:secondary; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; C546639:Pik3ca protein, mouse; D018631:ras Proteins