The essential clathrin adaptor protein complex-2 is tumor suppressive specifically in vivo

The microenvironment is a rich source of new cancer targets. While whole-genome CRISPR/Cas9 screens have identified vulnerabilities in cultured cells, it is a challenge to use this approach in tumors to interrogate the microenvironment. To this end, we screened a panel of pancreatic cancer lines grown in culture versus as tumors with a phosphatidylinositol metabolism CRISPR/Cas9 library. This revealed the Adaptor Protein complex-2 (AP2) of clathrin-mediated endocytosis behaves as common essential in culture but tumor suppressive in vivo. These polar-opposite phenotypes were attributed to different microenvironments. In culture, AP2 loss reduces endocytosis of transferrin and iron import. In tumors, alternative iron transport pathways allow pro-tumor signaling to manifest. In the most sensitive case, AP2 loss reprograms the plasma membrane proteome, retaining integrins on the surface leading to downregulation of the tumor-suppressor PTEN. Analysis of human tumors suggests a similar tumor suppressive activity. AP2 may foreshadow other proteins unique to the tumor-microenvironment.