<scp>MIF</scp> confers survival advantage to pancreatic <scp>CAFs</scp> by suppressing interferon pathway‐induced p53‐dependent apoptosis
Voddu Suresh, Pujarini Dash, Sujit Suklabaidya, Krushna Chandra Murmu, Prakash Kumar Sasmal, Gajendra M. Jogdand, Deepti Parida, Manisha Sethi, Biswajit Das, Debasish Mohapatra, Subha Saha, Punit Prasad, Abhay R. Satoskar, Shantibhusan Senapati
Abstract
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.