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. BerryHiroaki 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

114 Scopus citations


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.

Original languageAmerican English
Pages (from-to)6262-6280.e26
Issue number26
StatePublished - 22 Dec 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 The Authors


  • adenoma
  • colorectal cancer
  • cytotoxic
  • differentiation
  • metaplasia
  • multiplex
  • polyp
  • serrated
  • single-cell RNA-seq
  • stem cells


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