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

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 (HS) proteoglycan 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 HS chains. Here, by means of CRISPR/Cas9-mediated knockout and doxycycline-inducible short hairpin RNA-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 strongly decreased autocrine Wnt/β-catenin pathway activity and 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 (Fzd). Furthermore, in an HS-dependent fashion, syndecan-1 also binds osteoblast-produced R-spondin, which represses Fzd degradation by activation of LGR4, an R-spondin receptor aberrantly expressed on MM cells. Costimulation 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 in the treatment of MM.

CD138/syndecan–1 in pancreatic solid and pseudopapillary neoplasms

“…The relevance of the observed expression pattern is difficult to determine. However, this finding is not surprising as CD138 is reported to be a promoter of Wnt/beta-catenin signalling in multiple myeloma cells, with beta-catenin expression being an important diagnostic marker for SPNs 2. The expression pattern we have observed, which is membrane and cytoplasmic in the SPN cells and laterobasal in the pancreatic duct cell membrane, parallels that of CD56/neural cell adhesion molecule (NCAM), used as indicator of a neuroendocrine differentiation.…”

Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles

“…Syndecan-1 can regulate Wnt/β-catenin signaling in development and tumorigenesis by presenting Wnt ligands to the cognate receptor (57)(58)(59). This study provides a new level of understanding of how syndecan-1 controls Wnt signaling and the pathological consequences associated with disturbances in this pathway.…”

Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells

“…Interestingly an alternative mode of action for RSPO2 and RSPO3 has recently emerged that potentiates the WNT/b-catenin pathway through an interaction with heparan sulfate proteoglycans (HSPG) 33 . In Xenopus, RSPO3 has been shown to interact with Syndecan4 to induce noncanonical (PCP) signalling 29 and Syndecan1 has been suggested to present WNT and Rspondins in multiple myeloma 34 . Further analysis will be needed to identify the proteins responsible for mediating R-spondin action in the kidney.…”