Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps
Updated April 3, 2023Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.
Robert J CoffeyEpithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: robert.coffey@vumc.org.
Martha J ShrubsoleVanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: martha.shrubsole@vanderbilt.edu.martha.shrubsole@vanderbilt.edu
Ken S LauProgram in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: ken.s.lau@vanderbilt.edu.ken.s.lau@vanderbilt.edu
Bob Chen1
Cherie' R Scurrah2
Eliot T McKinley2
Alan J Simmons2
Marisol A Ramirez-Solano3
Xiangzhu Zhu4
Nicholas O Markham5
Cody N Heiser1
Paige N Vega2
Andrea Rolong2
Hyeyon Kim2
Quanhu Sheng3
Julia L Drewes6
Yuan Zhou3
Austin N Southard-Smith2
Yanwen Xu2
James Ro2
Angela L Jones7
Frank Revetta8
Lynne D Berry3
Hiroaki Niitsu9
Mirazul Islam2
Karin Pelka10
Matan Hofree11
Jonathan H Chen12
Siranush Sarkizova13
Kimmie Ng14
Marios Giannakis15
Genevieve M Boland16
Andrew J Aguirre15
Ana C Anderson17
Orit Rozenblatt-Rosen11
Aviv Regev18
Nir Hacohen19
Kenta Kawasaki20
Toshiro Sato20
Jeremy A Goettel21
William M Grady22
Wei Zheng4
M Kay Washington8
Qiuyin Cai4
Cynthia L Sears6
James R Goldenring23
Jeffrey L Franklin24
Timothy Su25
Won Jae Huh8
Simon Vandekar3
Joseph T Roland26
Qi Liu3
Robert J Coffey27
Martha J Shrubsole28
Ken S Lau (Principal Investigator)29
1Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
3Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
4Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
5Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
6Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
7Vanderbilt Technologies for Advanced Genomics, Vanderbilt University Medical Center, Nashville, TN, USA.
8Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
9Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.
10Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
11Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
12Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
13Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
14Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
15Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
16Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
17Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
18Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
19Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA.
20Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan.
21Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
22Clinical Research Division, Fred Hutchinson Cancer Research Center, and Gastroenterology Division, University of Washington School of Medicine, Seattle, WA, USA.
23Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
24Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.
25Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
26Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
27Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: robert.coffey@vumc.org.
28Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: martha.shrubsole@vanderbilt.edu.
29Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: ken.s.lau@vanderbilt.edu.
Rachel Schwartz
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Analysis Portals
CZ CELLxGENE
UCSC Cell BrowserProject Label
HtanPreCancerAltasSpecies
Homo sapiens
Sample Type
specimens
Anatomical Entity
colon
Organ Part
8 organ parts
Selected Cell Types
Unspecified
Disease Status (Specimen)
4 disease statuses
Disease Status (Donor)
polyp of colon
Development Stage
human adult stage
Library Construction Method
TruDrop
Nucleic Acid Source
single cell
Paired End
falseAnalysis Protocol
analysis_protocol_1, analysis_protocol_2File Format
4 file formats
Cell Count Estimate
68.3kDonor Count
106csv309 file(s)h5ad9 file(s)rds3 file(s)xlsx1 file(s)