**Preface to "In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application"**

Recent years have witnessed an unprecedented expansion of therapeutic options for colorectal cancer (CRC), with several molecularly targeted agents now established in clinical practice. Moreover, many new approaches are currently under evaluation, aimed at targeting different aspects of tumor biology including proliferating and quiescent cancer stem cells, antitumor immunity, tumor–microenvironment interactions, cancer metabolism, and cancer-associated epigenetic modifications. Advancements of high-throughput molecular analyses keep unveiling new details of the CRC molecular landscape contributing to identifying novel targets, to define improved methods for patients'classification and to achieve a better tuning of personalized therapies. However, despite increasing knowledge of the molecular mechanisms underlying CRC, the likelihood of approval (LOA) of new anticancer drugs entering clinical trial is still lower than 10% according to estimates (1, 2). The reason for this disconnection between basic/translational research and the related clinical outcomes resides, at least in part, in the limitations of preclinical models currently available for CRC. In fact, increasingly sophisticated experimental systems recapitulating CRC in vitro and in vivo, such as organoids and patient-derived xenografts (PDXs), are characterized by both intriguing complexities and intrinsic limitations, some of which are currently beginning to be understood. In this scenario, it is equally necessary to fully understand the potential of existing preclinical CRC models and to develop and validate novel tools for anticancer therapies. In this Special Issue, we have collected original research papers and reviews collectively depicting the current state and the perspectives of CRC models for preclinical and translational research. Original research papers published in this issue focus on some of the hottest topics in CRC research such as circulating tumor cells, epigenetic regulation of stemness states, new therapeutic targets, molecular CRC classification and experimental CRC models such as organoids and PDXs. Additionally, four reviews on CRC stem cells, immunotherapy and drug discovery provide an updated viewpoint on key topics linking benchtop to bedside research in CRC.

1. Hay, M., D. W. Thomas, J. L. Craighead, C. Economides and J. Rosenthal (2014). "Clinical development success rates for investigational drugs."Nature Biotechnology 32(1): 40-51.

2. Wong, C. H., K. W. Siah and A. W. Lo (2018). "Estimation of clinical trial success rates and related parameters."Biostatistics 20(2): 273-286.

> **Marta Baiocchi and Ann Zeuner** *Editors*
