TY - JOUR T1 - Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer JF - bioRxiv DO - 10.1101/2021.03.24.436532 SP - 2021.03.24.436532 AU - Winston R. Becker AU - Stephanie A. Nevins AU - Derek C. Chen AU - Roxanne Chiu AU - Aaron Horning AU - Rozelle Laquindanum AU - Meredith Mills AU - Hassan Chaib AU - Uri Ladabaum AU - Teri Longacre AU - Jeanne Shen AU - Edward D. Esplin AU - Anshul Kundaje AU - James M. Ford AU - Christina Curtis AU - Michael P. Snyder AU - William J. Greenleaf Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/03/25/2021.03.24.436532.abstract N2 - 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. ER -