Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer [article]

Winston R. Becker, Stephanie A. Nevins, Derek C. Chen, Roxanne Chiu, Aaron Horning, Rozelle Laquindanum, Meredith Mills, Hassan Chaib, Uri Ladabaum, Teri Longacre, Jeanne Shen, Edward D. Esplin (+5 others)
2021 bioRxiv   pre-print
ABSTRACTTo 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
more » ... criptional 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.
doi:10.1101/2021.03.24.436532 fatcat:h6shdx33xrhjjj5ma6utqguaom