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
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.
Datasets
1. Discovery (DIS) set of human colorectal tumor: Epithelial
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Validation (Val) set of human colorectal tumor: Epithelial
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stage3590 cells 56-year-old human stage3432 cells 70-year-old human stage2828 cells 58-year-old human stage2287 cells 51-year-old human stage2138 cells 71-year-old human stage2108 cells 72-year-old human stage2048 cells 67-year-old human stage1959 cells 68-year-old human stage1929 cells 74-year-old human stage1219 cells 55-year-old human stage911 cells 60-year-old human stage655 cells 53-year-old human stage163 cells 3. VAL and DIS datasets: Non-Epithelial
Metadata
Cell_Type
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Source data
https://cellxgene.cziscience.com/collections/a48f5033-3438-4550-8574-cdff3263fdfd
Alias names
HTAN VUMC, phs002371, PMID34910928, PMC8941949
Cite this study
Chen, B., Cherie’R, S., McKinley, E.T., Simmons, A.J., Ramirez-Solano, M.A., Zhu, X., Markham, N.O., Heiser, C.N., Vega, P.N., Rolong, A. and Kim, H., 2021. Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell, 184(26), pp.6262-6280. https://doi.org/10.1016/j.cell.2021.11.031
