Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer
Becker, W. R.; Nevins, S. A.; Chen, D. C.; Chiu, R.; Horning, A.; Laquindanum, R.; Mills, M.; Chaib, H.; Ladabaum, U.; Longacre, T.; Shen, J.; Esplin, E. D.; Kundaje, A.; Ford, J. M.; Curtis, C.; Snyder, M. P.; Greenleaf, W. J.
Show abstract
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.
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