CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway
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Updated: Apr 20, 2026
Author Spotlight: Analyzing Bone Marrow Microenvironment in Murine Hematological Malignancies
Published on: November 10, 2023
1Department of Radiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Abstract:
As the second most prevalent hematologic malignancy, multiple myeloma (MM) remains incurable and relapses due to intrinsic or acquired drug resistance. Therefore, new therapeutic strategies that target molecular mechanisms responsible for drug resistance are attractive. Interactions of tumor cells with their surrounding microenvironment impact tumor initiation, progression and metastasis, as well as patient prognosis. This cross-talk is bidirectional. Tumor cells can also attract or activate tumor-associated stromal cells by releasing cytokines to facilitate their growth, invasion and metastasis. The effect of myeloma cells on bone marrow stromal cells (BMSCs) has not been well studied. In our study, we found that higher stiffness of BMSCs was not a unique characteristic of BMSCs from MM patients (M-BMSCs). BMSCs from MGUS (monoclonal gammopathy of undetermined significance) patients were also stiffer than the BMSCs from healthy volunteers (N-BMSCs). The stiffness of M-BMSCs was enhanced when cocultured with myeloma cells. In contrast, no changes were seen in myeloma cell-primed MGUS- and N-BMSCs. Interestingly, our data indicated that CD138⁻ myeloma cells, but not CD138⁺ cells, regulated M-BMSC stiffness. SDF-1 was highly expressed in the CD138⁻ myeloma subpopulation compared with that in CD138⁺ cells. Inhibition of SDF-1 using AMD3100 or knocking-down CXCR4 in M-BMSCs blocked CD138⁻ myeloma cells-induced increase in M-BMSC stiffness, suggesting a crucial role of SDF-1/CXCR4. AKT inhibition attenuated SDF-1-induced increases in M-BMSC stiffness. These findings demonstrate, for the first time, CD138⁻ myeloma cell-directed cross-talk with BMSCs and reveal that CD138⁻ myeloma cells regulate M-BMSC stiffness through SDF-1/CXCR4/AKT signaling.
Insights
Multiple myeloma (MM) cells alter bone marrow stromal cell (BMSC) stiffness via the SDF-1/CXCR4/AKT pathway. This discovery reveals a novel therapeutic target for overcoming drug resistance in MM patients.
Area of Science:
- Hematologic Malignancies
- Cancer Biology
- Cellular Microenvironment
Background:
- Multiple myeloma (MM) is a prevalent, incurable hematologic malignancy often associated with drug resistance.
- Tumor microenvironment interactions significantly influence cancer progression and prognosis.
- The specific effects of myeloma cells on bone marrow stromal cells (BMSCs) remain underexplored.
Purpose of the Study:
- To investigate the bidirectional cross-talk between myeloma cells and BMSCs.
- To elucidate the mechanisms by which myeloma cells influence BMSC properties, particularly stiffness.
- To identify molecular pathways involved in myeloma-BMSC interactions.
Main Methods:
- Comparative analysis of BMSC stiffness from healthy volunteers (N-BMSCs), monoclonal gammopathy of undetermined significance (MGUS) patients, and MM patients (M-BMSCs).
- Co-culture experiments to assess changes in M-BMSC stiffness upon interaction with myeloma cells.
- Investigating the role of specific myeloma cell subpopulations (CD138⁻ vs. CD138⁺) and signaling pathways (SDF-1/CXCR4/AKT).
- Pharmacological inhibition (AMD3100) and genetic knockdown (CXCR4) were employed.
Main Results:
- BMSCs from both MGUS and MM patients exhibited increased stiffness compared to N-BMSCs.
- Co-culture with myeloma cells significantly enhanced M-BMSC stiffness, while MGUS- and N-BMSCs showed no change.
- CD138⁻ myeloma cells, but not CD138⁺ cells, were responsible for increasing M-BMSC stiffness.
- The SDF-1/CXCR4 signaling pathway was identified as crucial, with SDF-1 highly expressed in CD138⁻ myeloma cells.
- Inhibition of SDF-1 or CXCR4, and AKT signaling, blocked the myeloma-induced increase in BMSC stiffness.
Conclusions:
- CD138⁻ myeloma cells actively regulate M-BMSC stiffness through the SDF-1/CXCR4/AKT signaling axis.
- This represents a novel mechanism of tumor cell-stromal cell interaction in the myeloma microenvironment.
- Targeting this specific cross-talk pathway may offer new therapeutic strategies against drug-resistant multiple myeloma.
