Targeting the tetraspanin CD81 reduces cancer invasion and metastasis.

Proceedings of the National Academy of Sciences of the United States of America
Felipe Vences-CatalánShoshana Levy

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.

References

Jun 2, 2004·Nature Reviews. Cancer·Klaus Pantel, Ruud H Brakenhoff
Feb 3, 2005·Nature Reviews. Immunology·Shoshana Levy, Tsipi Shoham
Sep 2, 2008·Nature Reviews. Drug Discovery·Martin E Hemler
May 25, 2011·Mutation Research·Franziska van ZijlWolfgang Mikulits
Feb 8, 2014·Nature Reviews. Cancer·Martin E Hemler
Jun 30, 2016·Nature Reviews. Molecular Cell Biology·Ceniz ZihniMaria S Balda
Apr 15, 2017·Biochemical Society Transactions·Felipe Vences-CatalánShoshana Levy
May 28, 2019·The Journal of Experimental Medicine·Felipe Vences-CatalánShoshana Levy
Sep 9, 2019·Cellular Oncology (Dordrecht)·Naoki MizoshiriToshikazu Kubo
Jan 16, 2021·Science·Katherine J SusaStephen C Blacklow

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