CD44-downregulation in multiple myeloma inhibits cytoskeleton rearrangement through actin depolymerization

Area of Science:

• Hematology
• Cell Biology
• Cancer Research

Background:

• Multiple myeloma (MM) cells rely heavily on the bone marrow (BM) microenvironment for survival and proliferation.
• The intricate signaling pathways governing MM cell interactions with BM stromal cells are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying MM cell interactions with BM stromal cells using an in vitro coculture model.
• To identify key signaling pathways and molecular players involved in MM cell adhesion, migration, and proliferation within the BM microenvironment.

Main Methods:

• Utilized an in vitro coculture system with MM cells and HS5 BM-derived stromal cells.
• Quantified hyaluronic acid (HA) and interleukin-6 (IL-6) secretion, and measured CD44 and F-actin expression and polymerization.
• Analyzed hyaluronan synthase (HAS) isoform mRNA expression, particularly HAS3.
• Investigated Rac1 signaling and its co-localization with CD44.
• Assessed the impact of CD44 silencing on MM cell behavior.

Main Results:

• Coculture stimulated HA and IL-6 secretion and increased CD44 and F-actin polymerization in MM cells.
• HAS3 mRNA expression was significantly upregulated in MM cells upon coculture.
• MM cells in direct contact with HS5 cells showed enhanced proliferation and formed membrane protrusions enriched with CD44.
• Rac1 signaling was found to be critical for CD44-mediated cytoskeletal rearrangements.
• Silencing CD44 reduced F-actin polymerization, migration, and adhesion of MM cells to HS5.

Conclusions:

• The hyaluronic acid (HA)/CD44/F-actin signaling axis plays a crucial role in mediating multiple myeloma cell migration and adhesion within the bone marrow microenvironment.
• CD44 emerges as a potential therapeutic target for disrupting the MM-BM interaction and inhibiting disease progression.