MIF confers survival advantage to pancreatic CAFs by suppressing interferon pathway‐induced p53‐dependent apoptosis

The FASEB JournalVolume 36, Issue 8 e22449 RESEARCH ARTICLE MIF confers survival advantage to pancreatic CAFs by suppressing interferon pathway-induced p53-dependent apoptosis Voddu Suresh, Voddu Suresh Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Regional Centre for Biotechnology, Faridabad, IndiaSearch for more papers by this authorPujarini Dash, Pujarini Dash Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorSujit Suklabaidya, Sujit Suklabaidya Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorKrushna Chandra Murmu, Krushna Chandra Murmu Regional Centre for Biotechnology, Faridabad, India Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorPrakash K. Sasmal, Prakash K. Sasmal Department of General Surgery, All India Institute of Medical Sciences, Bhubaneswar, IndiaSearch for more papers by this authorGajendra M. Jogdand, Gajendra M. Jogdand Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorDeepti Parida, Deepti Parida Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Regional Centre for Biotechnology, Faridabad, IndiaSearch for more papers by this authorManisha Sethi, Manisha Sethi Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Regional Centre for Biotechnology, Faridabad, IndiaSearch for more papers by this authorBiswajit Das, Biswajit Das Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorDebasish Mohapatra, Debasish Mohapatra Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Kalinga Institute of Industrial Technology, Bhubaneswar, IndiaSearch for more papers by this authorSubha Saha, Subha Saha Regional Centre for Biotechnology, Faridabad, India Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorPunit Prasad, Punit Prasad Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorAbhay Satoskar, Abhay Satoskar Department of Microbiology, The Ohio State University, Columbus, Ohio, USASearch for more papers by this authorShantibhusan Senapati, Corresponding Author Shantibhusan Senapati senapati@ils.res.in orcid.org/0000-0001-7108-8255 Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Correspondence Shantibhusan Senapati, Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Nalco Square, Bhubaneswar 751 023, India. Email: senapati@ils.res.inSearch for more papers by this author Voddu Suresh, Voddu Suresh Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Regional Centre for Biotechnology, Faridabad, IndiaSearch for more papers by this authorPujarini Dash, Pujarini Dash Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorSujit Suklabaidya, Sujit Suklabaidya Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorKrushna Chandra Murmu, Krushna Chandra Murmu Regional Centre for Biotechnology, Faridabad, India Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorPrakash K. Sasmal, Prakash K. Sasmal Department of General Surgery, All India Institute of Medical Sciences, Bhubaneswar, IndiaSearch for more papers by this authorGajendra M. Jogdand, Gajendra M. Jogdand Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorDeepti Parida, Deepti Parida Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Regional Centre for Biotechnology, Faridabad, IndiaSearch for more papers by this authorManisha Sethi, Manisha Sethi Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Regional Centre for Biotechnology, Faridabad, IndiaSearch for more papers by this authorBiswajit Das, Biswajit Das Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorDebasish Mohapatra, Debasish Mohapatra Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Kalinga Institute of Industrial Technology, Bhubaneswar, IndiaSearch for more papers by this authorSubha Saha, Subha Saha Regional Centre for Biotechnology, Faridabad, India Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorPunit Prasad, Punit Prasad Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaSearch for more papers by this authorAbhay Satoskar, Abhay Satoskar Department of Microbiology, The Ohio State University, Columbus, Ohio, USASearch for more papers by this authorShantibhusan Senapati, Corresponding Author Shantibhusan Senapati senapati@ils.res.in orcid.org/0000-0001-7108-8255 Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India Correspondence Shantibhusan Senapati, Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Nalco Square, Bhubaneswar 751 023, India. Email: senapati@ils.res.inSearch for more papers by this author First published: 15 July 2022 https://doi.org/10.1096/fj.202101953R Pujarini Dash and Sujit Suklabaidya have contributed equally. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract The presence of activated pancreatic stellate cells (PSCs) in the pancreatic ductal adenocarcinoma (PDAC) microenvironment plays a significant role in cancer progression. Macrophage migration inhibitory factor (MIF) is overexpressed in PDAC tissues and expressed by both cancer and stromal cells. The pathophysiological role of MIF in PDAC-associated fibroblasts or PSCs is yet to be elucidated. Here we report that the PSCs of mouse or cancer-associated fibroblast cells (CAFs) of human expresses MIF and its receptors, whose expression gets upregulated upon LPS or TNF-α stimulation. In vitro functional experiments showed that MIF significantly conferred a survival advantage to CAFs/PSCs upon growth factor deprivation. Genetic or pharmacological inhibition of MIF also corroborated these findings. Further, co-injection of mouse pancreatic cancer cells with PSCs isolated from Mif−/− or Mif+/+ mice confirmed the pro-survival effect of MIF in PSCs and also demonstrated the pro-tumorigenic role of MIF expressed by CAFs in vivo. Differential gene expression analysis and in vitro mechanistic studies indicated that MIF expressed by activated CAFs/PSCs confers a survival advantage to these cells by suppression of interferon pathway induced p53 dependent apoptosis. DISCLOSURES The authors declare no conflict of interest. Open Research DATA AVAILABILITY STATEMENT The RNA-seq data related to this study is deposited in the ArrayExpress database at EMBL-EBI under accession number E-MTAB-9392 (https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-9392). Supporting Information Filename Description fsb222449-sup-0001-FigureS1.pdfPDF document, 4.1 MB Figure S1 fsb222449-sup-0002-FigureS2.pdfPDF document, 2.1 MB Figure S2 fsb222449-sup-0003-FigureS3.pdfPDF document, 2.4 MB Figure S3 fsb222449-sup-0004-FigureS4.pdfPDF document, 329.8 KB Figure S4 fsb222449-sup-0005-FigureS5.pdfPDF document, 4.7 MB Figure S5 fsb222449-sup-0006-FigureS6.pdfPDF document, 330.3 KB Figure S6 fsb222449-sup-0007-FigureS7.pdfPDF document, 3.1 MB Figure S7 fsb222449-sup-0008-FigureS8.pdfPDF document, 10.8 MB Figure S8 fsb222449-sup-0009-FigureS9.pdfPDF document, 5 MB Figure S9 fsb222449-sup-0010-TableS10.docxWord 2007 document , 17 KB Table S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume36, Issue8August 2022e22449 RelatedInformation