Journal Article

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

Laquindanum, Rozelle, Mills, Meredith, Becker, Winston R., Guha, Tuhin K., Greenleaf, William J., Ford, James M., Horning, Aaron M., Chen, Derek C., Longacre, Teri, Snyder, Michael P., Shen, Jeanne, Curtis, Christina, Chiu, Roxanne, Ladabaum, Uri, Kundaje, Anshul, Esplin, Edward D., Chaib, Hassan, Nevins, Stephanie A.

2022

Overview

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 single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or 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 homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of 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. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps. Single-cell ATAC-seq and RNA-seq profiling traces the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC). A large proportion of polyp and CRC cells show a stem-like phenotype.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/176 / 631/208/191 / 631/208/200 / 631/67 / 631/67/1504 / Accessibility / Adenoma - genetics / Adenoma - pathology / Adenomatous polyposis coli / Agriculture / Animal Genetics and Genomics / Antigen-presenting cells / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cell Transformation, Neoplastic - genetics / Chromatin / Colon / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Composition / Datasets / DNA methylation / DNA Methylation - genetics / Epigenetics / Fibroblasts / Gene expression / Gene Function / Generalized linear models / Genetic transformation / Genomics / Hepatocyte nuclear factor 4 / Homeostasis / Human Genetics / Humans / Immunoregulation / Lymphocytes / Lymphocytes T / Mutation / Phenotypes / Polyps / Runx1 protein / Single-Cell Analysis / Stems / Transcriptomes / Tumors