Special Issue on Cancer and Regenerative Medicine

The convergence of cancer biology and regenerative medicine has created a rapidly evolving research landscape in which engineered models, biomimetic systems, and advanced analytical approaches^1-4 are reshaping how tumor progression, metastasis, and therapeutic response are studied. Cancer both exploits and disrupts regenerative processes— including tissue remodeling, vascularization, immune interactions, and stem cell dynamics—making tissue engineering a powerful framework for investigating disease mechanisms and developing new treatments. This Special Issue, as will be published in two separate Parts, highlights emerging strategies that leverage regenerative medicine concepts to model cancer complexity across scales, from cellular heterogeneity to tissue-level microenvironments.

In Part 1, contributions (1) focus on the development of increasingly sophisticated biomimetic models that capture key aspects of native tissue architecture, and (2) emphasize engineered microenvironments designed to probe tumor behavior within defined biophysical contexts. Lolli and co-workers ⁵ present an integrated human in vitro model of endochondral ossification incorporating mineralizing cartilage, vascular networks, and osteoclasts, providing a platform with relevance for skeletal disease and bone metastasis research. Similarly, van den Beucken and co-workers ⁶ introduce a humanized bone metastasis model combining vital human bone tissue with metastatic cancer cells across ex vivo and in vivo settings, demonstrating the promise and remaining challenges of physiologically relevant metastasis models. Further, Freeman & Slater ⁷ extend the concept of a designed tumor microenvironment through brain-mimetic niches that model brain-tropic, triple-negative breast cancer metastasis, demonstrating how biochemical and degradative properties of the niche shape tumor phenotype. From the perspective of biophysical effects on tumor behavior, Zustiak and co-workers ⁸ developed a dual-stiffness hydrogel system that enables observation of glioblastoma migration across stiffness interfaces, revealing directional invasion patterns linked to matrix mechanics.Together, these studies highlight how regenerative strategies enable reconstruction of complex multicellular niches critical for studying tumor–host interactions in an engineered microenvironment.

In Part 2, Sharma and co-workers ⁹ introduce a chemically defined, PEG-based three-dimensional lung tumor model that addresses a critical challenge in cancer tissue engineering: benchmarking engineered systems against in vivo biology. By combining transcriptomic profiling with pathway-level analyses, this work demonstrates that tumor cells cultured in synthetic hydrogels adopt gene expression programs that more closely resemble xenograft tumors than conventional two-dimensional cultures, including restoration of key pathways related to proliferation, immune signaling, and stress responses. Importantly, this study provides a quantitative framework for assessing model fidelity, moving beyond phenotypic comparisons toward molecular benchmarking.

Beyond experimental modeling of the extracellular matrix and physical microenvironment, Part 2 of this special issue also highlights the importance of cell-cell interactions and recent advances in resolving tumor heterogeneity and dynamic cell states. Demonstrating the importance of cell-cell interactions using a model of glioblastoma spheroids cultured in 3D, matrix-derived hydrogels, Harley and co-workers ¹⁰ show that spheroid size is a critical experimental variable influencing invasion patterns and drug response. Seeking to better resolve how heterogenous populations of cancer cells interact with a tumor, Brock and co-workers ¹¹ apply clonal lineage tracing coupled with single-cell transcriptomics to identify stable invasive programs and compensatory clonal dynamics in triple-negative breast cancer. This work illustrates how integrating high-resolution analytical tools with engineered systems can reveal mechanisms underlying invasion and therapeutic resistance.

Collectively, the studies in this Special Issue demonstrate the growing maturity of cancer tissue engineering as a field positioned at the intersection of regenerative medicine, biomaterials science, and systems biology. Increasing model complexity, improved human relevance, and integration with single-cell and quantitative approaches are enabling deeper mechanistic insight while supporting translational applications such as drug screening and precision oncology. Emerging approaches that combine controlled biomaterial platforms with rigorous molecular benchmarking represent an important step toward standardizing engineered tumor models and improving their predictive value.

As regenerative medicine principles continue to inform cancer research, future efforts will likely focus on multi-scale integration, longitudinal modeling of disease evolution, and standardized platforms that enhance reproducibility and clinical relevance. We hope this Special Issue stimulates further interdisciplinary collaboration and advances the development of engineered systems that more faithfully capture the dynamic biology of cancer.