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

Evans, Michael1; Leung, Kevin1; Porten, Sima1; Salangsang, Fernando1; Wells, James1; Chou, Jonathan1; Loudermilk, Rita1; Ding, Chien-Kuang1; Steri, Veronica1; Camara Serrano, Juan Antonio1; Greenland, Nancy1; Delaveris, Corleone1; Pandey, Apurva1; Remesh, Soumya1; Peters-Clarke, Trenton1; Delavan, Henry1; Wang, Chunyue1; Chu, Carissa1; Ling, Jesse1; Dougherty, William1; Ganjave, Snehal1

Published Feb 28, 2026 on Dryad. https://doi.org/10.5061/dryad.z612jm6r4

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Abstract

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.