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

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.

Mitogen‐activated protein kinase activity drives cell trajectories in colorectal cancer

“…Here, we define six transcriptome‐based states of CRC cells, termed stem/TA‐like, goblet cell‐like, and TC1‐4, that have differential activities of oncogenic pathways. Individual stem cell markers such as OLFM4 or CD44 varied in expression between the stem/TA‐cell‐like and TC1‐4 clusters and were also found overexpressed in clusters of colorectal polyp and cancer cell of another study (preprint: Becker et al , 2021). Based on these transcriptional patterns, it appears that no unique stem cell signature exists in CRC and that Wnt, YAP, and MAPK activities together can maintain different cell states that may act as functional equivalents of stem cells that can sustain cancer growth.…”

Maintaining and escaping feedback control in hierarchically organised tissue: a case study of the intestinal epithelium

“…The copyright holder for this preprint this version posted June 11, 2021. ; https://doi.org/10.1101/2021.06.11.448040 doi: bioRxiv preprint intestinal epithelial tissue on the single-cell level in order to answer the question, whether we are indeed able to identify similar cellular subpopulation and differentiation gradients in both of them. Very recent research seems to in fact suggest exactly this [51]. If this holds, tracking the numbers of different cell types over time during development and after perturbations would yield valuable data for validating and more accurately parametrising the model derived in this work.…”

Ultra high-throughput whole-genome methylation sequencing reveals trajectories in precancerous polyps to early colorectal adenocarcinoma

“…By integrating ATAC-seq and WGMS datasets we demonstrated the resemblance in these signals both in terms of correlated changes in specific regulatory elements as well as similar gene sets emerging from the cluster analysis (Fig 5c ; Becker et al 2022 36 ). These similarities highlight the fact that these two assays mirror similar underlying biological changes and to suggest that WGMS results can serve as proxy to the underlying chromatin state.…”

“…The availability of ATAC-seq data for similar FAP samples enables us to follow the dynamics of DNA methylation and chromatin accessibility in detail. We examined the methylation changes at distal regulatory elements by integrating accessibility data defined using scATAC from a parallel dataset of benign-dysplasia-adenocarcinoma tumor progression in FAP patients 36 . We first filtered the accessible peaks by distance from CpG islands and transcription start site (>1 kb from both) and by the number of CpGs in each peak (>3 CpGs per peak; Supplementary Fig 4e).…”