%0 Journal Article %A Winston R. Becker %A Stephanie A. Nevins %A Derek C. Chen %A Roxanne Chiu %A Aaron Horning %A Rozelle Laquindanum %A Meredith Mills %A Hassan Chaib %A Uri Ladabaum %A Teri Longacre %A Jeanne Shen %A Edward D. Esplin %A Anshul Kundaje %A James M. Ford %A Christina Curtis %A Michael P. Snyder %A William J. Greenleaf %T Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer %D 2021 %R 10.1101/2021.03.24.436532 %J bioRxiv %P 2021.03.24.436532 %X To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated 451,886 single-cell chromatin accessibility profiles and 208,557 single-cell transcriptomes from 48 polyps, 27 normal tissues, and 6 CRCs collected from patients with and without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from normal to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T-cells, and a subtype of FOX-regulated pre-cancer associated fibroblasts. In the cancerous state, we observe T-cell exhaustion, RUNX1-regulated cancer associated fibroblasts, and increasing accessibility associated with HNF4A motifs in epithelia. Methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.Competing Interest StatementW.J.G. is a consultant for 10x Genomics and Guardant Health, Co-founder of Protillion Biosciences, and is named on patents describing ATAC-seq. M.P.S. is a cofounder and scientific advisor for Personalis, Qbio, January.ai, Filtricine, Mirvie, Protos and an advisor for Genapsys. %U https://www.biorxiv.org/content/biorxiv/early/2021/03/25/2021.03.24.436532.full.pdf