TY - JOUR
T1 - Syndecan-1 promotes Wnt/β-catenin signaling in multiple myeloma by presenting Wnts and R-spondins
AU - Ren, Zemin
AU - van Andel, Harmen
AU - de Lau, Wim
AU - Hartholt, Robin B.
AU - Maurice, Madelon M.
AU - Clevers, Hans
AU - Kersten, Marie José
AU - Spaargaren, Marcel
AU - Pals, Steven T.
PY - 2018
Y1 - 2018
N2 - 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
AB - 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
U2 - https://doi.org/10.1182/blood-2017-07-797050
DO - https://doi.org/10.1182/blood-2017-07-797050
M3 - Article
C2 - 29212806
SN - 0006-4971
VL - 131
SP - 982
EP - 944
JO - Blood
JF - Blood
IS - 9
ER -