Faculty Collaboration Database

Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis. Oncogene 2020 Sep;39(38):6129-6137

Date

08/19/2020

Pubmed ID

32807917

Pubmed Central ID

PMC7502515

DOI

10.1038/s41388-020-01424-7

Scopus ID

2-s2.0-85089539324 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

Activation of cancer-associated fibroblasts (CAFs) and ensuing desmoplasia play an important role in the growth and progression of solid tumors. Here we demonstrate that, within colon and pancreatic ductal adenocarcinoma tumors, efficient stromagenesis relies on downregulation of the IFNAR1 chain of the type I interferon (IFN1) receptor. Expression of the fibroblast activation protein (FAP) and accumulation of the extracellular matrix (ECM) was notably impaired in tumors grown in the Ifnar1^S526A (SA) knock-in mice, which are deficient in IFNAR1 downregulation. Primary fibroblasts from these mice exhibited elevated levels of Smad7, a negative regulator of the transforming growth factor-β (TGFβ) pathway. Knockdown of Smad7 alleviated deficient ECM production in SA fibroblasts in response to TGFβ. Analysis of human colorectal cancers revealed an inverse correlation between IFNAR1 and FAP levels. Whereas growth of tumors in SA mice was stimulated by co-injection of wild type but not SA fibroblasts, genetic ablation of IFNAR1 in fibroblasts also accelerated tumor growth. We discuss how inactivation of IFNAR1 in CAFs acts to stimulate stromagenesis and tumor growth.

Author List

Cho C, Mukherjee R, Peck AR, Sun Y, McBrearty N, Katlinski KV, Gui J, Govindaraju PK, Puré E, Rui H, Fuchs SY

Author

Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Biomarkers, Tumor
Cancer-Associated Fibroblasts
Cell Line, Tumor
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Interferon Type I
Mice
Neoplasms
Receptor, Interferon alpha-beta
Signal Transduction
Tumor Microenvironment