Autophagolysosomal exocytosis inverts Src kinase and other N-myristoylated proteins onto the cell surface in cancer

Overexpression of the protoconogene Src is common to a wide variety of cancers. Here, we demonstrate that Src is noncanonically inverted onto the cell surface in cancer both in vitro and in vivo. We identify autophagolysosomal exocytosis (ALE) as a secretory mechanism prominent in cancer cell lines and show that Src is the prototypical example for a family of membrane-anchored proteins that are inverted by this process. Furthermore, we show that this extracellular membrane-associated Src (eSrc) is present in primary tumors and that anti-Src antibody-based therapies mediate tumor cell killing in vitro and in vivo. Collectively, this work presents a secretory mechanism by which intracellular N-myristoylated proteins, prototypically Src, are inverted on the cell surface in cancer and can be targeted with antibody therapeutics.