DLBCL-microenvironment interactions: cytokine profiling and ECM-mediated ibrutinib resistance in a 3D bone-based...

Area of Science:

• Oncology
• Cell Biology
• Biomaterials

Background:

• Diffuse large B-cell lymphoma (DLBCL) often relapses due to microenvironment-mediated drug resistance.
• Preclinical models of bone marrow involvement in DLBCL are limited, especially those replicating the extracellular matrix (ECM).
• Understanding DLBCL-ECM interactions is crucial for overcoming therapeutic resistance.

Purpose of the Study:

• To evaluate the impact of bone-derived extracellular matrix (ECM) interactions on DLBCL cell behavior and drug sensitivity.
• To investigate the role of 3D culture models in recapitulating microenvironment-driven resistance.
• To explore the mechanisms underlying ECM-mediated resistance to ibrutinib.

Main Methods:

• Utilized a decellularized human bone-derived 3D scaffold to culture four DLBCL cell lines (OCI-LY1, OCI-LY18, RIVA, NU-DUL-1).
• Performed functional assays and cytokine profiling under both 2D and 3D culture conditions.
• Assessed ibrutinib sensitivity and apoptosis induction in DLBCL cells cultured on the 3D ECM scaffold.

Main Results:

• The 3D ECM model significantly remodeled the DLBCL secretome, upregulating pro-migratory chemokines.
• ECM engagement enhanced DLBCL migration and colonization, establishing a tumor-microenvironment feedback loop.
• DLBCL cells adhering to the ECM exhibited reduced ibrutinib-induced apoptosis in 3D cultures, linked to AKT/mTOR pathway activation.

Conclusions:

• Direct tumor-matrix interactions in a 3D bone ECM model induce reversible ibrutinib resistance in DLBCL.
• The ECM dynamically regulates drug response and reshapes the cytokine milieu in DLBCL.
• Physiologically relevant 3D models are essential for studying microenvironment-driven resistance and guiding therapeutic strategies.