RT Journal Article
SR Electronic
T1 Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.24.436532
DO 10.1101/2021.03.24.436532
A1 Winston R. Becker
A1 Stephanie A. Nevins
A1 Derek C. Chen
A1 Roxanne Chiu
A1 Aaron Horning
A1 Rozelle Laquindanum
A1 Meredith Mills
A1 Hassan Chaib
A1 Uri Ladabaum
A1 Teri Longacre
A1 Jeanne Shen
A1 Edward D. Esplin
A1 Anshul Kundaje
A1 James M. Ford
A1 Christina Curtis
A1 Michael P. Snyder
A1 William J. Greenleaf
YR 2021
UL http://biorxiv.org/content/early/2021/03/25/2021.03.24.436532.abstract
AB 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.