Project Summary This is a competitive renewal application for a SPORE in Gastrointestinal (GI) Cancers originating from the GI Malignancies Program of the Dana-Farber/Harvard Cancer Center (DF/HCC). Since its inception in 2007, the SPORE has established a thriving culture of inter-institutional collaboration that has united basic, clinical, and population scientists into a highly productive translational enterprise. The ability to attract and retain researchers from diverse disciplines has fostered fundamental discoveries in cancer biology, innovative translational hypotheses, and cutting-edge clinical trials. The SPORE has also maintained a central focus on developing a large cadre of new investigators, building on a successful model of interdisciplinary, cross- campus cooperation that serves as a nidus for inter-SPORE relationships and other collaborations. Moreover, the SPORE has created invaluable research resources, such as the Tissue, PDX and Organoid Repository and clinical, pathology, and genomics databases that collectively accelerate translational investigation. Each of the current projects has achieved or exceeded its translational goals, providing a foundation for programmatic studies, including independent large-scale collaborative initiatives. Building on this progress, the DF/HCC GI SPORE seeks to continue to translate biological and technological advances into improvements in the prevention and treatment of GI malignancies. The overarching objectives of a renewed SPORE are to: 1) Define optimal genomic and functional strategies, including integration of cell-free (cf)DNA profiling (Projects 1-4), to predict drug responsiveness and improve diagnostics, prognostics, and clinical decisions. 2) Elucidate the interplay between oncogenic mutations, targeted therapy, and anti-tumor immunity to inform cancer biology and improve the outcome of patients with GI cancers (Projects 1,3, 4). 3) Define mechanisms of resistance to novel targeted therapies and hence identify new approaches to overcome resistance and better select the patients most likely to respond to therapy (Projects 1-4). 4) Enhance study of deadly GI cancers that, despite rising incidence, remain under- studied (Project 2, 4). 5) Encourage collaboration and promote academic rigor by providing clinical specimens, fostering core technologies and resources, and hosting regular research meetings and seminars focused on GI cancers. 6) Provide mentorship and training for young GI cancer researchers and recruit leading translational investigators from other fields through Career Enhancement and Developmental Project Awards.