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

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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 Ifnar1S526A (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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Fig. 1: Inactivation of IFNAR1 in the nonimmune tumor stroma promotes tumor growth.
Fig. 2: Downregulation of IFNAR1 in fibroblasts induces the stromagenic switch.
Fig. 3: Inactivation of type I IFN signaling in CAFs promotes tumor growth.

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Acknowledgements

This work was supported by the by the NIH/NCI R01 grants CA092900 (to SYF), CA240814 (to SYF and HR), and P01 CA217805 (to EP). Additional support from T32 CA115299 (to NM) and T32 CA009140 (to KVK) is also greatly appreciated. We would like to thank Dr. Ben Z. Stanger and Jinyang Li for generously gifting mouse PDA cells and advising us in the generation of PDAC subcutaneous tumors. We also thank Drs. Xin-Hua Feng and Yi Yu and for generously gifting the pLKO.1 plasmids, and providing the protocols for generating the aforementioned lentiviruses.

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Authors and Affiliations

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

    Christina Cho, Riddhita Mukherjee, Noreen McBrearty, Kanstantsin V. Katlinski, Jun Gui, Priya K. Govindaraju, Ellen Puré & Serge Y. Fuchs

  2. Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Amy R. Peck, Yunguang Sun & Hallgeir Rui

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  1. Christina Cho
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  2. Riddhita Mukherjee
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Correspondence to Serge Y. Fuchs.

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Cho, C., Mukherjee, R., Peck, A.R. et al. Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis. Oncogene 39, 6129–6137 (2020). https://doi.org/10.1038/s41388-020-01424-7

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