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

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

doi:10.1038/s41588-022-01088-x

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

Nat Genet. 2022 Jul;54(7):985-995. doi: 10.1038/s41588-022-01088-x. Epub 2022 Jun 20.

Authors

Winston R Becker^#^{1

2}, Stephanie A Nevins^#¹, Derek C Chen¹, Roxanne Chiu¹, Aaron M Horning¹, Tuhin K Guha¹, Rozelle Laquindanum³, Meredith Mills³, Hassan Chaib¹, Uri Ladabaum⁴, Teri Longacre⁵, Jeanne Shen⁵, Edward D Esplin¹, Anshul Kundaje^{1

6}, James M Ford^{1

3}, Christina Curtis^{1

3

7}, Michael P Snyder⁸, William J Greenleaf^{9

10

11}

Affiliations

¹ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
² Program in Biophysics, Stanford University, Stanford, CA, USA.
³ Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
⁴ Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, CA, USA.
⁵ Department of Pathology, Stanford University, Stanford, CA, USA.
⁶ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁷ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. mpsnyder@stanford.edu.
⁹ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. wjg@stanford.edu.
¹⁰ Department of Applied Physics, Stanford University, Stanford, CA, USA. wjg@stanford.edu.
¹¹ Chan Zuckerberg Biohub, San Francisco, CA, USA. wjg@stanford.edu.

^# Contributed equally.

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 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adenoma* / genetics
Adenoma* / pathology
Cell Transformation, Neoplastic / genetics
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / pathology
DNA Methylation / genetics
Humans
Single-Cell Analysis

Abstract

Publication types

MeSH terms

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