Speaker
Description
Understanding how spatial arrangements of diverse cell types within the tumor microenvironment (TME) influence cancer progression remains one of the foremost challenges in oncology. To address this, we have developed a suite of single-cell bioprinting technologies that enable engineering of tumor models with unprecedented spatial resolution in both two and three dimensions. Leveraging a microfluidic dispensing system and two-photon hydrogel printing, we first established a method for bioprinting annotated 2D maps of breast tumors at single-cell fidelity. By replicating the histology of ductal carcinoma in situ (DCIS) with precise XY deposition of epithelial, stromal, and immune cells—including MCF10A, MDA-MB-231, primary fibroblasts, macrophages, and mesenchymal stem cells—we recreated native tissue architecture with an average print deviation of only 2.4 µm (Figure). These 2D reconstructions allowed real-time tracking of cell dynamics, single cell spatial transcriptomic validation of tumor response, revealing how shifts in stromal phenotype and spatial organization drive early malignant behavior. Building on this framework, we extended our platform into 3D, generating high resolution 3D bioprinted tumor avatars that recapitulate the cellular complexity and organization of human tumors across all spatial axes. These avatars contain up to seven cell types, recapitualting the exact arrangement of tumor neighborhoods of native patient biopsies, and retain high viability, proliferation, and functional heterogeneity. By using patient-derived tumor biopsy maps, we enabled tissue maturation, cell-cell junction formation, and matrix remodeling with or without extracellular matrix supplements (Figure). Perturbation experiments with TGF-β1 revealed fibroblast-driven matrix reorganization and epithelial elongation, validating the avatars’ responsiveness and utility for mechanistic studies. We validated the spatially-defined respose of these tumors in comparison to organoids, which inherently lack controlled spatial arragnement, and demonstrate the importance of biopritning spatially defined tumor microenvironemnts to elucidate the complex biology of cancer. Together, these bioprinted models offer a transformative approach to studying the spatial determinants of tumor behavior with unmatched control and resolution. By bridging annotated patient data with controllable experimental systems, our 2D and 3D single-cell bioprinting platforms set the stage for high-content functional interrogation of the TME, and may pave the way for precision oncology, spatial therapeutics, and predictive digital twins in cancer research.
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