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Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer

Corleone S Delaveris1, Rita P Loudermilk2, Apurva Pandey3

  • 1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.

Science (New York, N.Y.)
|March 12, 2026
PubMed

Insights

Proto-oncogene Src is found on the cancer cell surface via autophagolysosomal exocytosis (ALE). This extracellular Src (eSrc) in tumors can be targeted by antibody therapies for cancer treatment.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Overexpression of the proto-oncogene Src is frequently observed in various cancers.
  • The precise localization and transport mechanisms of Src in cancer cells remain incompletely understood.

Purpose of the Study:

  • To investigate the noncanonical translocation and cell surface localization of Src in cancer.
  • To identify the secretory pathway responsible for extracellular Src (eSrc) transport.
  • To evaluate the therapeutic potential of targeting eSrc.

Main Methods:

  • In vitro and in vivo cancer models.
  • Analysis of autophagolysosomal exocytosis (ALE) in cancer cell lines.
  • Detection of extracellular membrane-associated Src (eSrc) in primary tumors.
  • Evaluation of anti-Src antibody-based therapies in cell culture and mouse xenograft models.

Main Results:

  • Src is noncanonically translocated and inverted onto the cell surface in cancer.
  • Autophagolysosomal exocytosis (ALE) is a key secretory mechanism for transporting Src and other membrane-anchored proteins to the cell exterior.
  • Extracellular membrane-associated Src (eSrc) is present in primary human tumors.
  • Anti-Src antibody therapies demonstrated efficacy in killing tumor cells in vitro and reducing tumor growth in vivo.

Conclusions:

  • Intracellular proteins, such as N-myristoylated Src, can be topologically inverted and presented on the cancer cell surface.
  • This extracellular Src (eSrc) represents a vulnerable target for antibody-based cancer therapeutics.

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