Targeting the tetraspanin CD81 reduces cancer invasion and metastasis

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.

Temporal extracellular vesicle protein changes following intraarticular treatment with integrin α10β1-selected mesenchymal stem cells in equine osteoarthritis

“…However, the tetraspanin CD81 is involved in providing a scaffold enabling the recruitment of complementary proteins, enabling the function of many cellular processes. CD81 expression has been strongly associated with cancerous pathologies, and has been shown to promote tumor growth and metastasis in human melanoma, while its knockdown in osteosarcoma models has reduced tumor progression ( 45 ). Across all experimental groups the sham control remained significantly lower than the experimental group at all time points, suggestive of a minimal effect from the arthroscopy in the sham control groups.…”

Machine learning-assisted elucidation of CD81–CD44 interactions in promoting cancer stemness and extracellular vesicle integrity

“…Nevertheless, other tetraspanin proteins, such as TSPAN8 and CD9, may promote cancer self-renewal in colorectal cancer ( Zhu et al, 2019 ) and glioblastoma ( Podergajs et al, 2016 ), respectively. A potential anti-CD81 therapeutic strategy was identified to block the pro-metastatic effect of CD81 in animal studies ( Vences-Catalán et al, 2021 ). CD44 can also interact with other transmembrane proteins such as TM4SF5, resulting in elevated properties of self-renewal and circulating capacity in hepatocarcinoma cells ( Lee et al, 2015 ).…”

ALCAM/CD166 Is Involved in the Binding and Uptake of Cancer-Derived Extracellular Vesicles

“…The monoclonal antibodies used in this research were purified by protein A- or protein G-affinity chromatography, according to their isotype as described previously [ 52 ]. These antibodies included mAb 5A6 (anti-CD81 tetraspanin, kindly provided by Dr. Shoshana Levy, Stanford University, CA, USA) [ 53 ], mAb Lia1/2 (anti-β1 integrin; kindly provided by Dr. Francisco Sánchez-Madrid, Hospital de la Princesa, Madrid, Spain) [ 54 , 55 ], commercial mAbs TS2/16 (anti-β1 integrin, Santa Cruz Biotechnology sc-53711) P1D6 (anti-α5 integrin, Abcam ab78614), mAbs (generated and characterized in our laboratory) PAINS-10 (anti-CD9 tetraspanin), PAINS-15 (anti-ALCAM) and 3B3 (anti-ALCAM) [ 32 , 52 ].…”