Publications by authors named "Priya K Govindaraju"

2 Publications

  • Page 1 of 1

Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis.

Oncogene 2020 09 17;39(38):6129-6137. Epub 2020 Aug 17.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

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 (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.
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http://dx.doi.org/10.1038/s41388-020-01424-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502515PMC
September 2020

Fibroblast Activation Protein Regulates Lesion Burden and the Fibroinflammatory Response in Apoe-Deficient Mice in a Sexually Dimorphic Manner.

Am J Pathol 2020 05 19;190(5):1118-1136. Epub 2020 Feb 19.

Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia Pennsylvania. Electronic address:

Fibroblast activation protein (FAP) has been established as an inducible and mesenchymal cell-specific mediator of disease progression in cancer and fibrosis. Atherosclerosis is a fibroinflammatory disease, and FAP was previously reported to be up-regulated in human atherosclerotic plaques compared with normal vessel. We investigated the spatial and temporal distribution of Fap-expressing cells in a murine model of atherosclerosis and used a genetic approach to determine if and how Fap affected disease progression. Fap was found to be expressed predominantly on vascular smooth muscle cells in lesions of athero-prone Apoe mice. Global deletion of Fap (Fap) in Apoe mice accelerated atherosclerotic disease progression in both males and females, with the effect observed earlier in males. Sex-specific effects on lesion morphology were observed. Relative levels of extracellular matrix, fibrotic, and inflammatory cell content were comparable in lesions in male mice regardless of Fap status. In contrast, lesions in Fap female mice were characterized by a more fibrotic composition due to a reduction in inflammation, specifically a reduction in Mox macrophages. Combined, these data suggest that Fap restrains the progression of atherosclerosis and may contribute to the sexually dimorphic susceptibility to atherosclerosis by regulating the balance between inflammation (an indicator of vulnerability to plaque rupture) and fibrosis (an indicator of plaque stability).
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http://dx.doi.org/10.1016/j.ajpath.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237832PMC
May 2020