read_status: unread
type: paper
title: "Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps"
year: 2021
authors:
- "Chen, Bob"
- "Scurrah, Cherie’ R."
- "McKinley, Eliot T."
- "Simmons, Alan J."
- "Ramirez-Solano, Marisol A."
- "Zhu, Xiangzhu"
- "Markham, Nicholas O."
- "Heiser, Cody N."
- "Vega, Paige N."
- "Rolong, Andrea"
- "Kim, Hyeyon"
- "Sheng, Quanhu"
- "Drewes, Julia L."
- "Zhou, Yuan"
- "Southard-Smith, Austin N."
- "Xu, Yanwen"
- "Ro, James"
- "Jones, Angela L."
- "Revetta, Frank"
- "Berry, Lynne D."
- "Niitsu, Hiroaki"
- "Islam, Mirazul"
- "Pelka, Karin"
- "Hofree, Matan"
- "Chen, Jonathan H."
- "Sarkizova, Siranush"
- "Ng, Kimmie"
- "Giannakis, Marios"
- "Boland, Genevieve M."
- "Aguirre, Andrew J."
- "Anderson, Ana C."
- "Rozenblatt-Rosen, Orit"
- "Regev, Aviv"
- "Hacohen, Nir"
- "Kawasaki, Kenta"
- "Sato, Toshiro"
- "Goettel, Jeremy A."
- "Grady, William M."
- "Zheng, Wei"
- "Washington, M. Kay"
- "Cai, Qiuyin"
- "Sears, Cynthia L."
- "Goldenring, James R."
- "Franklin, Jeffrey L."
- "Su, Timothy"
- "Huh, Won Jae"
- "Vandekar, Simon"
- "Roland, Joseph T."
- "Liu, Qi"
- "Coffey, Robert J."
- "Shrubsole, Martha J."
- "Lau, Ken S."
journal: "Cell"
doi: "10.1016/j.cell.2021.11.031"
url: "https://linkinghub.elsevier.com/retrieve/pii/S0092867421013817"
project:
- IGP
system:
- intestinal_epithelium
- colonic_crypt
- luminal_surface
- immune_microenvironment
disease:
- colorectal_cancer
- colorectal_polyps
genes:
- apc
- braf
- cdx2
processes:
- stem_cell_expansion
- gastric_metaplasia
- cell_state_transition
- antigen_presentation
- immune_cell_recruitment
methods:
- single_cell_rna_seq
- multiplex_immunofluorescence
- multiplex_immunohistochemistry
- regulon_analysis
- mouse_genetic_models
key_findings:
- wnt_driven_stem_cell_expansion
- metaplasia_from_differentiated_cells
- immune_activation_precedes_hypermutation
- stemness_associated_with_immune_suppression
limitations:
- limited_longitudinal_sampling
- incomplete_non_epithelial_coverage
- unresolved_metaplasia_triggers
relevance:
- redefines_precancer_origins
- links_cell_state_to_immunity
- informs_crc_surveillance
concepts:
- Cell-State-Dependent Tumorigenesis
- Metaplasia-Driven Neoplasia
- Stemness-Immune Tradeoff
tags:
- sc_atlas
- precancer
- epithelial_plasticity
- tumor_microenvironment
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. Wepresent 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.
Adenomas initiate via WNT-driven stem cell expansion
Serrated polyps originate from differentiated cells via gastric metaplasia
Cytotoxic immune infiltration precedes hypermutation in serrated lesions
Stem-like tumor cells suppress antigen presentation
Tumor cell-of-origin dictates immune microenvironment
Single-cell RNA sequencing of human polyps and CRCs
SCENIC regulon-based cell state inference
Multiplex IF/IHC for spatial immune mapping
Genetically engineered mouse models (Apc vs Braf; stem vs non-stem origin)
Tumorigenesis is cell-state–dependent, not mutation-first
Differentiated cells retain immune-activating capacity
Acquisition of stemness correlates with immune evasion
Figure 2: scRNA-seq identification of stem-like vs metaplastic programs
Figure 3: Spatial evidence for luminal surface origin of serrated lesions
Figure 6: Cytotoxic immune enrichment in serrated polyps
No longitudinal tracking of individual polyps
Limited mechanistic resolution of metaplasia triggers
Partial immune compartment sampling