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INTERNATIONAL CONGRESS OF

CancerGenetics

• A Practical Framework for Modeling and Engineering the Bone Marrow Tumor Microenvironment, Focusing on Key Parameters and Therapeutic Applications

• Azar Rezaei,¹ Sadaf Vahdat,^2,* Niloofar Allamehzadeh,³
  1. Faculty of Interdisciplinary Science and Technology, Tarbiat Modares University
  2. Applied Cell Sciences Division, Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University
  3. Faculty of Interdisciplinary Science and Technology, Tarbiat Modares University
  
  
  
• Introduction: Hematologic malignancies are a group of cancers that disrupt hematopoiesis in the bone marrow (BM) and are generally classified into three categories: leukemia, lymphoma, and myeloma. The BM tumor microenvironment (BM-TME) is a complex and dynamic niche in which physicochemical conditions, extracellular matrix (ECM) properties, stromal and immune interactions, and spatial gradients collectively influence malignant cell survival, disease progression, and therapeutic response. Conventional two-dimensional (2D) cultures fail to reproduce many of these features, limiting their ability to model microenvironment-mediated drug resistance and accurately evaluate therapeutic strategies. Consequently, increasing efforts have focused on developing three-dimensional (3D) and engineered BM-mimetic models. However, selecting an appropriate modeling strategy requires consideration of which microenvironmental features need to be reproduced for a specific research or therapeutic application.
• Methods: To this end, published studies on the biology, engineering, and in vitro modeling of the BM-TME in hematological malignancies were reviewed. Microenvironmental features were categorized into physicochemical parameters (oxygen tension/hypoxia, pH, nutrients, and metabolites), biophysical parameters (ECM composition, stiffness, porosity, and architecture), cellular and signaling components (malignant, stromal, endothelial, and immune cells), and transport-related characteristics (oxygen, nutrient, and drug gradients). Current modeling approaches were classified into modified 2D cultures, scaffold-based and scaffold-free 3D systems, multicellular co-cultures, organoid-like models, bioreactors, microfluidic platforms, and advanced engineered systems.
• Results: The reviewed evidence indicates that no single parameter or model can fully reproduce the BM-TME. Scaffold-based and hydrogel systems provide greater control over matrix composition, architecture, and mechanical properties, whereas spheroid, organoid-like, and multicellular models are particularly useful for investigating cell-cell and tumor-stroma interactions. Microfluidic and dynamic platforms offer additional control over oxygen, nutrient, and drug gradients and enable investigation of transport and treatment responses. Importantly, specific BM-TME features may also serve as design cues for therapeutic development. Hypoxia, extracellular pH, matrix properties, cellular interactions, and transport gradients can be exploited as potential targets or triggers for microenvironment-responsive drug delivery and controlled therapeutic release. These models therefore provide complementary platforms for drug screening, investigation of microenvironment-mediated resistance, and evaluation of targeted or stimuli-responsive therapeutic strategies.
• Conclusion: In summary, a practical approach to BM-TME modeling should move beyond the simple transition from 2D to 3D, and instead match the selected modeling platform to the biological or therapeutic question. Systematic integration of physicochemical, biophysical, cellular, and transport-related parameters may enable more physiologically relevant models for drug screening and provide a rational framework for developing microenvironment-targeted and responsive drug delivery systems for translational research.
• Keywords: Bone marrow tumor microenvironment, hematologic malignancies, 3D in vitro models, drug screening