Journal article
Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis
Oncogene, Vol.39(38), pp.6129-6137
09/17/2020
DOI: 10.1038/s41388-020-01424-7
PMCID: PMC7502515
PMID: 32807917
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 theIfnar1(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-beta (TGF beta) pathway. Knockdown of Smad7 alleviated deficient ECM production in SA fibroblasts in response to TGF beta. 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.
Details
- Title: Subtitle
- Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis
- Creators
- Christina Cho - University of PennsylvaniaRiddhita Mukherjee - University of PennsylvaniaAmy R. Peck - Medical College of WisconsinYunguang Sun - Medical College of WisconsinNoreen McBrearty - University of PennsylvaniaKanstantsin V. Katlinski - University of PennsylvaniaJun Gui - University of PennsylvaniaPriya K. Govindaraju - University of PennsylvaniaEllen Pure - University of PennsylvaniaHallgeir Rui - Medical College of WisconsinSerge Y. Fuchs - University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.39(38), pp.6129-6137
- DOI
- 10.1038/s41388-020-01424-7
- PMID
- 32807917
- PMCID
- PMC7502515
- NLM abbreviation
- Oncogene
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Publisher
- Springer Nature
- Number of pages
- 9
- Grant note
- CA092900; CA240814; P01 CA217805 / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 09/17/2020
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984949511302771
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