Engineering breast cancer models in vitro with 3D bioprinting

Abstract Human tissues are exquisitely organized across a daunting span of length-scales. In breast cancer, tumor cells dismantle and reprogram this multiscale tissue organization to drive disease progression and evade therapy. The extracellular matrix (ECM), tissue mechanics, and dimensionality play commanding roles in tumor organization. Consequently, three-dimensional (3D) in vitro models have emerged as versatile platforms for deconstructing cancer biology. However, in vitro models remain inadequate to reproduce the heterogeneous spatial relationships that underlie tumor behavior. 3D bioprinting is emerging as a powerful strategy for reconstructing tissue organization from the top-down. It may hold the potential to unify the tunability of in vitro culture with the tissue-level fidelity of in vivo models. In this chapter, we develop a broad overview of the history, progress, and challenges of 3D in vitro models of breast cancer: from pioneering studies with decellularized ECMs, to the design of synthetic ECMs inspired by nature, and to the latest progress in 3D bioprinting tissue models. As we illustrate, 3D in vitro models have unveiled a window into the intricate design rules for engineered tumor microenvironments, and biomaterials engineers have compiled a versatile arsenal of molecular tools to confront these complexities. Many of these advancements have been translated to bioprinting techniques, which continue to improve in cell viability, throughput, and spatial resolution, thereby yielding directed assembly of multicellular structures that have yet to be realized from traditional approaches. Unfortunately, many biomaterials still lack the full ensemble of biophysical features of the native tumor ECM, and the ability to orthogonally tune such features remains a formidable challenge. For bioprinting, significant challenges remain ahead for producing structures that mimic tissue-level functions, such as perfusable tumor vascularization, which are essential to bridging in vitro therapy models with in vivo realities. If these challenges are overcome, bioprinting 3D breast cancer models may yield unprecedented opportunities for discovery platforms that mirror human biology and exploit the flexibility of in vitro models.