Gastrointestinal (GI) cancers, including esophageal adenocarcinoma, pancreatic ductal adenocarcinoma, and colorectal cancer, are among the most common and challenging cancers. They are particularly deadly when diagnosed at late, metastatic stages. Treatment efficacy varies widely, and not all patients respond the same way. Recurrences, often as metastases, are common, diminishing quality of life, complicating treatment, and almost always precluding cure. Precision oncology may contribute to a solution: tailoring treatments to the unique molecular characteristics of each tumor. In this thesis, we explore preclinical leads to broaden precision medicine's reach in GI cancers. We delve into the topics of tumor heterogeneity (“why does not everyone respond to therapy equally?”) and acquired resistance (“why is the response only temporary?”).Cancer treatments act differently in different people, highlighting the importance of understanding the heterogeneity between tumors. This topic is discussed in Part 1: Tumor heterogeneity (chapters 2 to 7). One promising approach to describe intertumor heterogeneity is to use computational methods to categorize gene expression profiles from different patients in so-called molecular subtypes. Importantly, these molecular subtypes often have clinical meaning as they can prognosticate overall survival or predict treatment outcome. In Part 2: Acquired Resistance (chapter 8 and 9), we discuss the phenomenon where a cancer, initially sensitive to a particular therapy, gradually becomes resistant to that treatment over time. We did this in the context of neoadjuvant chemoradiation therapy in resectable esophageal adenocarcinoma
