Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps

Bob Chen; Cherie' R Scurrah; Eliot T McKinley; Alan J Simmons; Marisol A Ramirez-Solano; Xiangzhu Zhu; Nicholas O Markham; Cody N Heiser; Paige N Vega; Andrea Rolong; Hyeyon Kim; Quanhu Sheng; Julia L Drewes; Yuan Zhou; Austin N Southard-Smith; Yanwen Xu; James Ro; Angela L Jones; Frank Revetta; Lynne D Berry; Hiroaki Niitsu; Mirazul Islam; Karin Pelka; Matan Hofree; Jonathan H Chen; Siranush Sarkizova; Kimmie Ng; Marios Giannakis; Genevieve M Boland; Andrew J Aguirre; Ana C Anderson; Orit Rozenblatt-Rosen; Aviv Regev; Nir Hacohen; Kenta Kawasaki; Toshiro Sato; Jeremy A Goettel; William M Grady; Wei Zheng; M Kay Washington; Qiuyin Cai; Cynthia L Sears; James R Goldenring; Jeffrey L Franklin; Timothy Su; Won Jae Huh; Simon Vandekar; Joseph T Roland; Qi Liu; Robert J Coffey; Martha J Shrubsole; Ken S Lau

doi:10.1016/j.cell.2021.11.031

Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps

Cell. 2021 Dec 22;184(26):6262-6280.e26. doi: 10.1016/j.cell.2021.11.031. Epub 2021 Dec 14.

Authors

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 Lau²⁹

Affiliations

¹ Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
³ Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Epithelial 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.
⁶ Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Vanderbilt Technologies for Advanced Genomics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Epithelial 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.
¹⁰ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
¹¹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Broad 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.
¹³ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁵ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁶ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
¹⁸ Broad 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.
¹⁹ Broad 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.
²⁰ Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan.
²¹ Department 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.
²² Clinical Research Division, Fred Hutchinson Cancer Research Center, and Gastroenterology Division, University of Washington School of Medicine, Seattle, WA, USA.
²³ Epithelial 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.
²⁴ 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 Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁵ Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ Epithelial 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.
²⁸ Vanderbilt-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.
²⁹ Program 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.

Abstract

Colorectal 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.

Keywords: adenoma; colorectal cancer; cytotoxic; differentiation; metaplasia; multiplex; polyp; serrated; single-cell RNA-seq; stem cells.

Publication types

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

MeSH terms

Adaptive Immunity
Adenoma / genetics
Adenoma / pathology
Adult
Aged
Animals
Carcinogenesis / genetics
Carcinogenesis / pathology
Cell Death
Cell Differentiation
Colonic Polyps / genetics
Colonic Polyps / immunology
Colonic Polyps / pathology*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / immunology
Colorectal Neoplasms / pathology*
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Genetic Heterogeneity
Humans
Male
Mice
Middle Aged
Mutation / genetics
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
RNA-Seq
Reproducibility of Results
Single-Cell Analysis
Tumor Microenvironment* / immunology

Abstract

Publication types

MeSH terms

Grants and funding