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Syndecan-1 promotes Wnt/β-catenin signaling in multiple myeloma by presenting Wnts and R-spondins

Zemin Ren, Harmen van Andel, Wim de Lau, Robin B. Hartholt, Madelon M. Maurice, Hans Clevers, Marie José Kersten, Marcel Spaargaren and Steven T. Pals

Key points

  • HS chains decorating syndecan-1 promote autocrine and paracrine Wnt signaling in MM.

  • Loss of HS inhibits MM cell growth by attenuating Wnt signaling.

Abstract

Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells in the bone marrow (BM). Most MMs display aberrant Wnt/β-catenin signaling, which drives proliferation; however, they lack oncogenic Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts from the BM microenvironment. Expression of the heparan sulfate proteoglycan (HSPG) syndecan-1 is a hallmark of MM. Syndecan-1 is a critical player in the complex reciprocal interaction between MM cells and their BM niche, mediating growth factor/cytokine binding and signaling by its heparan sulfate (HS) chains. Here, by means of CRISPR/Cas9-mediated knockout and doxycycline-inducible shRNA-mediated knockdown of EXT1, a critical enzyme for HS polymerization, we demonstrate that the HS-chains decorating syndecan-1 mediate aberrant Wnt-pathway activation in MM. HS-deficient MM cells exhibited a strongly decreased autocrine Wnt/β-catenin pathway activity and a reduced Wnt-pathway-dependent proliferation. In addition, we demonstrate that Wnts bind to the HS side-chains of syndecan-1 and that this binding contributes to paracrine Wnt-pathway activation through the Wnt-receptor Frizzled. Furthermore, in a HS-dependent fashion, syndecan-1 also binds osteoblast-produced R-spondin, which represses Frizzled degradation by activation of LGR4, an R-spondin receptor aberrantly expressed on MM cells. Co-stimulation with R-spondin, and its binding to HS chains decorating syndecan-1, are indispensable for optimal stimulation of Wnt-signaling in MM. Taken together, our results identify syndecan-1 as a crucial component of the Wnt-signalosome in MM cells, binding Wnts and R-spondins to promote aberrant Wnt/β-catenin signaling and cell growth, and suggest HS and its biosynthetic enzymes as potential targets for the treatment of MM.

  • Submitted July 20, 2017.
  • Accepted December 1, 2017.