Extracellular Enolase-1 Promotes CAF-Associated Stromal Reprogramming via the Plasmin/TGF-β Axis in Multiple Myeloma

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Stromal remodeling in the tumor microenvironment is crucial for multiple myeloma (MM) progression and drug resistance.
• Extracellular enolase-1 (ENO1) is implicated in tumor progression, but its role in cancer-associated fibroblast (CAF)-mediated stromal reprogramming in MM is not well understood.

Purpose of the Study:

• To investigate the role of extracellular ENO1 in CAF-associated stromal reprogramming in MM.
• To evaluate the therapeutic potential of targeting extracellular ENO1 in bortezomib (BTZ)-resistant MM.

Main Methods:

• Co-culture of MM and bone marrow stromal cells (BMSCs) to assess ENO1 effects.
• Analysis of lactate production, viability, protein expression, and cytokine secretion.
• In vivo studies using a xenograft model of BTZ-resistant MM in NPG mice.
• Evaluation of an anti-ENO1 monoclonal antibody (HuL001) for therapeutic efficacy.

Main Results:

• Extracellular ENO1 promoted fibroblast activation protein expression via plasmin-mediated TGF-β activation, inducing a CAF phenotype with increased glycolysis and tumor-promoting cytokines.
• HuL001 inhibited ENO1-driven stromal reprogramming and reduced tumor-supportive activity in vivo.
• HuL001 in combination with lenalidomide overcame BTZ resistance in MM.

Conclusions:

• Extracellular ENO1 drives CAF-associated stromal reprogramming in the MM microenvironment through the ENO1/plasminogen/plasmin/TGF-β axis.
• Targeting extracellular ENO1 with HuL001 represents a potential therapeutic strategy to disrupt tumor-supportive stromal functions and overcome drug resistance in MM.