Modelling the complex nature of the tumor microenvironment: 3D tumor spheroids as an evolving tool

Cancer remains a serious burden in society and while the pace in the development of novel and more effective therapeutics is increasing, testing platforms that faithfully mimic the tumor microenvironment are lacking. With a clear shift from animal models to more complex in vitro 3D systems, spheroids emerge as strong options in this regard. Years of development have allowed spheroid-based models to better reproduce the biomechanical cues that are observed in the tumor-associated extracellular matrix (ECM) and cellular interactions that occur in both a cellâ cell and cell-ECM manner. Here, we summarize some of the key cellular interactions that drive tumor development, progression and invasion, and how successfully are these interactions recapitulated in 3D spheroid models currently in use in the field. We finish by speculating on future advancements in the field and on how these can shape the relevance of spherical 3D models for tumor modelling. Authors would like to acknowledge the fnancial support from the European Research Council through the Starting Grant “CapBed” (ERC-2018-STG-805411) and FCT/MCTES (Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia, e Ensino Superior) through the grant SFRH/BD/119756/2016 (D.B.R.). The authors would additionally like to thank the contributions to this work from the project “TERM RES Hub—Scientifc Infrastructure for Tissue Engineering and Regenerative Medicine”, reference PINFRA/22190/2016 (Norte-01-0145-FEDER-022190), funded by the Portuguese National Science Foundation (FCT) in cooperation with the Northern Portugal Regional Coordination and Development Commission (CCDR-N). Ultimately, we would like to equally acknowledge fnancial support fromhttps://doi.org/10.54499/ UIDB/50026/2020);https://doi.org/10.54499/UIDP/50026/2020) andhttps://doi. org/10.54499/LA/P/0050/2020).