Targeting the tetraspanin CD81 reduces cancer invasion and metastasis

Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2018961118. doi: 10.1073/pnas.2018961118.

Abstract

Tetraspanins are an evolutionary conserved family of proteins involved in multiple aspects of cell physiology, including proliferation, migration and invasion, protein trafficking, and signal transduction; yet their detailed mechanism of action is unknown. Tetraspanins have no known natural ligands, but their engagement by antibodies has begun to reveal their role in cell biology. Studies of tetraspanin knockout mice and of germline mutations in humans have highlighted their role under normal and pathological conditions. Previously, we have shown that mice deficient in the tetraspanin CD81 developed fewer breast cancer metastases compared to their wild-type (WT) counterparts. Here, we show that a unique anti-human CD81 antibody (5A6) effectively halts invasion of triple-negative breast cancer (TNBC) cell lines. We demonstrate that 5A6 induces CD81 clustering at the cell membrane and we implicate JAM-A protein in the ability of this antibody to inhibit tumor cell invasion and migration. Furthermore, in a series of in vivo studies we demonstrate that this antibody inhibits metastases in xenograft models, as well as in syngeneic mice bearing a mouse tumor into which we knocked in the human CD81 epitope recognized by the 5A6 antibody.

Keywords: JAM-A; immunotherapy; xenograft.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Breast Neoplasms / pathology*
  • Cell Adhesion Molecules / metabolism
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Epitopes / metabolism
  • Female
  • Humans
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Receptors, Cell Surface / metabolism
  • Tetraspanin 28 / metabolism*
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies
  • CD81 protein, human
  • Cell Adhesion Molecules
  • Epitopes
  • F11R protein, human
  • Receptors, Cell Surface
  • Tetraspanin 28