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 878920

Subject Categories

Cell Biology

Cell and Molecular Biology

Immunology in the medical area

DOI

10.3389/fonc.2022.878920

PubMed

35600339

More information

Latest update

6/9/2022 2