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

• Published in: The FASEB journal Vol. 36; no. 8; p. e22449
• Main Authors: Suresh, Voddu, Dash, Pujarini, Suklabaidya, Sujit, Murmu, Krushna Chandra, Sasmal, Prakash K, Jogdand, Gajendra M, Parida, Deepti, Sethi, Manisha, Das, Biswajit, Mohapatra, Debasish, Saha, Subha, Prasad, Punit, Satoskar, Abhay, Senapati, Shantibhusan
• Format: Journal Article
• Language: English
• Published: United States 01.08.2022
• Subjects: Animals; Apoptosis - genetics; Apoptosis - physiology; Cancer-Associated Fibroblasts - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor - metabolism; Cell Movement; Cell Proliferation; Humans; Interferons - metabolism; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Macrophage Migration-Inhibitory Factors - genetics; Macrophage Migration-Inhibitory Factors - metabolism; Mice; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Tumor Microenvironment; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; pancreatic stellate cells; CAFs; apCAFs; stromal cells; Treg; apoptosis; fibrosis
• ISSN: 1530-6860
• DOI: 10.1096/fj.202101953R

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.