Related Experiment Video

Updated: Sep 2, 2025

The Assembly and Application of 'Shear Rings': A Novel Endothelial Model for Orbital, Unidirectional and Periodic Fluid Flow and Shear Stress
09:20

The Assembly and Application of 'Shear Rings': A Novel Endothelial Model for Orbital, Unidirectional and Periodic Fluid Flow and Shear Stress

Published on: October 31, 2016

8.2K

EMD originates from hyaluronan-induced homophilic interactions of CD44 variant-expressing MM cells under shear stress

Jiro Kikuchi1, Nobuyuki Kodama2,3, Masataka Takeshita2,3

  • 1Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.

Blood Advances
|August 5, 2022
PubMed

Insights

Hyaluronan (HA) binding to CD44 on multiple myeloma (MM) cells promotes extramedullary disease (EMD) and proteasome inhibitor resistance. Targeting the HA-CD44 axis may prevent and treat EMD in MM patients.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Extramedullary disease (EMD) in multiple myeloma (MM) is linked to chemoresistance and poor prognosis.
  • The underlying mechanisms of EMD development in MM remain incompletely understood.
  • Identifying EMD mechanisms and therapeutic targets is crucial for improving MM patient outcomes.

Purpose of the Study:

  • To elucidate the mechanism of extramedullary disease (EMD) development in multiple myeloma (MM).
  • To investigate the role of hyaluronan (HA) and CD44 in EMD formation and chemoresistance.
  • To evaluate therapeutic strategies targeting the HA-CD44 axis for EMD in MM.

Main Methods:

  • Investigated HA-CD44 interactions in MM cells under physiological shear stress.
  • Utilized a syngeneic murine MM model with HA administration to recapitulate EMD development.
  • Assessed proteasome inhibitor (PI) resistance in HA-induced MM cell clusters in vitro and in vivo.
  • Examined the role of γ-secretase-mediated CD44 cleavage in PI resistance.
  • Evaluated the efficacy of anti-CD44 antibodies and γ-secretase inhibitors in preventing EMD and overcoming PI resistance.

Main Results:

  • Bone marrow stroma cell-derived HA induces MM cell clustering via CD44 binding, potentially leading to EMD.
  • HA administration in a murine MM model recapitulated EMD development in a CD44-dependent manner.
  • HA-induced MM cell clusters demonstrated resistance to proteasome inhibitors (PIs) through γ-secretase-mediated CD44 cleavage and transactivation of PI resistance genes.
  • Treatment with anti-CD44 antibody or γ-secretase inhibitors suppressed EMD development and prolonged survival in recipient mice by overcoming PI resistance.

Conclusions:

  • The HA-CD44 axis is a novel pathway driving EMD development in multiple myeloma (MM).
  • Targeting the HA-CD44 axis, including CD44 cleavage, offers a potential strategy for predicting, preventing, and treating EMD in MM.
  • This finding could significantly improve treatment outcomes for MM patients with extramedullary disease.

More Related Videos

On-Chip Endothelial Inflammatory Phenotyping12:43

On-Chip Endothelial Inflammatory Phenotyping

Published on: July 21, 2012

11.0K
A Multi-well Format Polyacrylamide-based Assay for Studying the Effect of Extracellular Matrix Stiffness on the Bacterial Infection of Adherent Cells11:51

A Multi-well Format Polyacrylamide-based Assay for Studying the Effect of Extracellular Matrix Stiffness on the Bacterial Infection of Adherent Cells

Published on: July 5, 2018

11.8K

Related Concept Videos

Cell-matrix's Response to Mechanical Forces01:13

Cell-matrix's Response to Mechanical Forces

In animal cells, the extracellular matrix allows cells within tissues to withstand external stresses and transmits signals from the outside of the cell to the inside. The extracellular matrix is extensive, and its composition varies between different types of tissues. For example, the reticular fibers and ground substance make up the ECM in loose connective tissue, while collagen and bone minerals make up the ECM of bone tissue. 
Anchoring junctions mechanically attach a cell to the...
2.7K
Adherens Junctions01:24

Adherens Junctions

Strong contact points between adjacent cells anchor them to each other, forming tissues. Such anchoring junctions are of two types –  adherens junctions and desmosomes. Adherens junctions are abundant in tissues such as  epithelium and endothelium, forming a continuous zone of adhesion called the adhesion belt. In other tissues, such as  heart muscle, they appear as clusters, linking the cells to produce coordinated heart muscle contraction.
Adherens Junctions are Dynamic
5.0K
Cadherins in Tissue Organization01:19

Cadherins in Tissue Organization

The cadherins are a superfamily of cell adhesion molecules comprising over 180 variants, with specific tissues expressing a particular combination of cadherin types. Cadherins generally exhibit homophilic binding; i.e., cadherins on one cell bind to cadherins of the same or closely related type on another cell. Thus, cells of the same type have a specific affinity to bind to each other and sort themselves into clusters to form tissues.
Cell Sorting During Development
Cell sorting plays an...
3.1K
Anchoring Junctions01:03

Anchoring Junctions

Anchoring junctions are multiprotein complexes that help cells connect to other cells and the extracellular matrix. Anchoring junctions are present on the lateral and basal surfaces of cells, providing strong and flexible connections. Focal adhesions are often formed due to cell interactions with the ECM substrata, which initiate signal transduction via kinase cascades and other mechanisms. Together, they provide stability and tissue integrity. There are three types of anchoring junctions:...
3.9K
Immunoglobulin-like Cell Adhesion Molecules01:31

Immunoglobulin-like Cell Adhesion Molecules

Immunoglobulin-like cell adhesion molecules or Ig-CAMs are a versatile group of cell surface glycoproteins belonging to the immunoglobulin protein superfamily. Ig-CAMs possess the characteristic immunoglobulin protein domains and other domains such as the fibronectin type III domain. The Ig domains are glycosylated to varying degrees in different Ig-CAMs.
Ig-CAMs exhibit either homophilic binding (to other Ig-CAMs) or heterophilic binding (to other ligands such as integrins). While most Ig-CAMs...
3.4K
Tension Response at Adherens Junctions01:26

Tension Response at Adherens Junctions

The adherens junctions that anchor cells together are multi-protein complexes that dynamically adapt to mechanical stimuli such as tensile forces and shear stress. Mechanosensory proteins in these junctions can sense such mechanical stimuli and undergo a shift in their conformation, resulting in an altered function — a process called mechanotransduction.
α-Catenin as a Mechanosensory Protein
The α-catenin of adherens junctions is an allosteric protein with three VH (vinculin...
2.8K