While advances in single cell genomics have helped to chart the cellular components of tumor ecosystems, it has been more challenging to characterize their specific spatial organization and functional interactions. Here, we combine single cell RNA-seq and spatial transcriptomics by Slide-seq, to create a detailed spatial map of healthy and dysplastic colon cellular ecosystems and their association with disease progression. We profiled an inducible genetic CRC mouse model that recapitulates key features of human CRC, assigned cell types and epithelial expression programs to spatial tissue locations in tumors, and computationally used them to identify the regional features spanning different cells in the same spatial niche. We find that tumors were organized in cellular neighborhoods, each with a distinct composition of cell subtypes, expression programs, and local cellular interactions. Three cellular neighborhood archetypes were associated with tumor progression, were active at the same time in different spatial parts of the same tumor, involved dysplasia-specific cellular layouts, and relied on distinct mechanisms: (1) inflammatory epithelial regions with endothelial cells and monocytes expressing angiogenesis, inflammation and invasion programs; (2) epithelial stem-like regions, associated with plasma and B cell activity; and (3) epithelial-to-mesenchymal transition (EMT) regions with dysplastic cells expressing a Wnt signaling program. Comparing to scRNA-seq and Slide-seq data from human CRC, we find that both cell composition and layout features were conserved in both species, with mouse archetypal neighborhoods correlated with malignancy and clinical outcome in human patient tumors, highlighting the relevance of our findings to human disease.Competing Interest StatementA.M. has served a consultant/advisory role for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, Flare Therapeutics, venBio Partners, BioNTech, Rheos Medicines and Checkmate Pharmaceuticals, is an equity holder in Asher Biotherapeutics and Abata Therapeutics, and has a sponsored research agreement with Bristol-Myers Squibb and Olink Proteomics. G.M.B. has sponsored research agreements with InterVenn Biosciences, Palleon Pharmaceuticals, Olink Proteomics, and Teiko Bio. G.M.B. is a consultant for Ankyra Therapeutics and InterVenn Bio. G.M.B. has been on scientific advisory boards for Merck, Iovance, Nektar Therapeutics, Instil Bio, and Ankyra Therapeutics. G.M.B. holds equity in Ankyra Therapeutics. N.H. holds equity in BioNTech and is a founder of Related Sciences/DangerBio. F.C. is a founder and holds equity in Curio Biosciences. O.Y. holds equity and is a SAB member of AVA Lifesciences. A.R. and O.R.-R. are co-inventors on patent applications filed by the Broad Institute for inventions related to single cell genomics. O.R.-R. has given numerous lectures on the subject of single cell genomics to a wide variety of audiences and in some cases, has received remuneration to cover time and costs. O.R.-R. is an employee of Genentech since October 19, 2020 and has equity in Roche. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until July 31, 2020. From August 1, 2020, A.R. is an employee of Genentech and has equity in Roche.