Corleone S. Delaveris, R. W. Loudermilk, Apurva Pandey, Soumya G. Remesh, Trenton M. Peters-Clarke, Snehal D. Ganjave, William J. N. Dougherty, Henry M. Delavan, Chunyue Wang, Jesse Ling, J. Camara Serrano, Fernando Salangsang, Chien‐Kuang Cornelia Ding, Nancy Greenland, Carissa E. Chu, Sima P. Porten, Veronica Steri, Jonathan Chou, Michael J. Evans, Kevin K. Leung, James A. Wells
Overexpression of the proto-oncogene Src is common to a wide variety of cancers. In this work, we found that Src is noncanonically translocated and inverted onto the cell surface in cancer, both in vitro and in vivo. We identified autophagolysosomal exocytosis (ALE) as a secretory mechanism prominent in cancer cell lines. Src represents the prototypical example of a family of membrane-anchored proteins that are transported by this process. Furthermore, this extracellular membrane–associated Src (eSrc) was found in primary tumors, and anti-Src antibody-based therapies mediated tumor cell killing in cell culture systems and in mouse xenograft models. Thus, intracellular N -myristoylated proteins, prototypically Src, can be topologically inverted onto the cell surface in cancer and targeted with antibody therapeutics.