Research Papers:

Autotaxin-β interaction with the cell surface via syndecan-4 impacts on cancer cell proliferation and metastasis

Raphael Leblanc, Debashish Sahay, Audrey Houssin, Irma Machuca-Gayet and Olivier Peyruchaud _

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Oncotarget. 2018; 9:33170-33185. https://doi.org/10.18632/oncotarget.26039

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Raphael Leblanc1,2,3,4, Debashish Sahay5, Audrey Houssin6,7, Irma Machuca-Gayet6,7 and Olivier Peyruchaud6,7

1Centre de Recherche en Cancérologie de Marseille, Marseille, France

2Institut Poli-Calmettes, Marseille, France

3INSERM, Unit 1068, Marseille, France

4University Aix-Marseille, Marseille, France

5Department of Medicine, Colombia University Medical Center, New York City, NY, USA

6INSERM, Unit 1033, Lyon, France

7Université Claude Bernard Lyon 1, Lyon, France

Correspondence to:

Olivier Peyruchaud, email: [email protected]

Keywords: autotaxin; heparan sulfate proteoglycans; syndecan-4; adhesion; metastasis

Received: June 02, 2018     Accepted: August 10, 2018     Published: September 04, 2018


Autotaxin (ATX) promotes cancer cell metastasis through the production of lysophosphatidic acid (LPA). ATX binds to αvβ3 integrins controlling metastasis of breast cancer cells. We screened a series of cancer cell lines derived from diverse human and mouse solid tumors for the capacity of binding to ATX and found only a modest correlation with their level of αvβ3 integrin expression. These results strongly suggested the existence of another cell surface ATX-interacting factor. Indeed, ATXα has been shown to bind heparan-sulfate chains because of its unique polybasic insertion sequence, although the biological significance is unknown. We demonstrated here, that among all cell surface heparan-sulfate proteoglycans, syndecan-4 (SDC4) was essential for cancer cell interaction with ATXβ but was restrained by heparan-sulfate chains. In addition, exogenous ATXβ-induced MG63 osteosarcoma cell proliferation required physical interaction of ATXβ with the cell surface via an SDC4-dependent mechanism. In a preclininal mouse model, targeting SDC4 on 4T1 mouse breast cancer cells inhibited early bone metastasis formation. Furthermore, SDC4-prometastatic activity was totally abolished in absence of ATX expression. In conclusion our results determined that ATX and SDC4 are engaged in a reciprocal collaboration for cancer cell metastasis providing the rational for the development of novel anti-metastasis therapies.

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