MIF confers survival advantage to pancreatic CAFs by suppressing interferon pathway-induced p53-dependent apoptosis.
Voddu SureshPujarini DashSujit SuklabaidyaKrushna Chandra MurmuPrakash K SasmalGajendra M JogdandDeepti ParidaManisha SethiBiswajit DasDebasish MohapatraSubha SahaPunit PrasadAbhay SatoskarShantibhusan SenapatiPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2022)
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.
Keyphrases
- cell cycle arrest
- induced apoptosis
- growth factor
- cell death
- endoplasmic reticulum stress
- oxidative stress
- stem cells
- endothelial cells
- papillary thyroid
- rheumatoid arthritis
- squamous cell carcinoma
- adipose tissue
- high glucose
- free survival
- genome wide
- immune response
- dna methylation
- young adults
- insulin resistance
- ultrasound guided
- wound healing