Cancer-Associated Fibroblasts and Squamous Epithelial Cells Constitute a Unique Microenvironment in a Mouse Model of Inflammation-Induced Colon Cancer
Journal article, 2022
The tumor microenvironment plays a key role in the pathogenesis of colorectal tumors and contains various cell types including epithelial, immune, and mesenchymal cells. Characterization of the interactions between these cell types is necessary for revealing the complex nature of tumors. In this study, we used single-cell RNA-seq (scRNA-seq) to compare the tumor microenvironments between a mouse model of sporadic colorectal adenoma (Lrig1(CreERT2/+);Apc(2lox14/+)) and a mouse model of inflammation-driven colorectal cancer induced by azoxymethane and dextran sodium sulfate (AOM/DSS). While both models develop tumors in the distal colon, we found that the two tumor types have distinct microenvironments. AOM/DSS tumors have an increased abundance of two populations of cancer-associated fibroblasts (CAFs) compared with APC tumors, and we revealed their divergent spatial association with tumor cells using multiplex immunofluorescence (MxIF) imaging. We also identified a unique squamous cell population in AOM/DSS tumors, whose origins were distinct from anal squamous epithelial cells. These cells were in higher proportions upon administration of a chemotherapy regimen of 5-Fluorouracil/Irinotecan. We used computational inference algorithms to predict cell-cell communication mediated by ligand-receptor interactions and downstream pathway activation, and identified potential mechanistic connections between CAFs and tumor cells, as well as CAFs and squamous epithelial cells. This study provides important preclinical insight into the microenvironment of two distinct models of colorectal tumors and reveals unique roles for CAFs and squamous epithelial cells in the AOM/DSS model of inflammation-driven cancer.
stem cells
tumor microenvironment
cancer associated fibroblasts (CAF)
inflammation
squamous cells
colorectal cancer
adaptive immunity
Author
Paige N. Vega
Vanderbilt University
Avlant Nilsson
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Massachusetts Institute of Technology (MIT)
Manu P. Kumar
Massachusetts Institute of Technology (MIT)
Hiroaki Niitsu
Vanderbilt University
Alan J. Simmons
Vanderbilt University
James Ro
Vanderbilt University
Jiawei Wang
Vanderbilt University
Zhengyi Chen
Vanderbilt University
Brian A. Joughin
Massachusetts Institute of Technology (MIT)
Wei Li
Vanderbilt University
Eliot T. McKinley
Vanderbilt University
Qi Liu
Vanderbilt University
Joseph T. Roland
Vanderbilt University
M. Kay Washington
Vanderbilt University
Robert J. Coffey
Vanderbilt University
Douglas A. Lauffenburger
Massachusetts Institute of Technology (MIT)
Ken S. Lau
Vanderbilt University
Frontiers in Oncology
2234943x (eISSN)
Vol. 12 878920Subject Categories
Cell Biology
Cell and Molecular Biology
Immunology in the medical area
DOI
10.3389/fonc.2022.878920
PubMed
35600339