Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42

Abstract

Inflammation is a major driver of tumor progression and metastasis, although the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown. Interleukin-6 (IL-6) is a potent proinflammatory cytokine that is elevated in individuals with pancreatic cancer (PDAC), is required for PDAC progression in mice, and increases tumor cell invasion Here, we provide insights into the mechanisms by which IL-6 activates tumor cell invasion. We found that IL-6 stimulation rapidly and robustly activates the small GTPase cell division cycle 42 (CDC42) in human PDAC cells and promotes the formation of premigratory filopodia. The CDC42 activation was required for IL-6-induced invasion as blocking CDC42 activity rendered the cells insensitive to IL-6's proinvasive effects. Loss of Janus kinase 2 (JAK2) or signal transducer and activator of transcription 3 (STAT3) prevented IL-6-mediated CDC42 activation, indicating that IL-6 activates CDC42 through both JAK2 and STAT3. However, the rapid activation of CDC42 suggested that this activation may be distinct from canonical STAT3-mediated transcriptional activation. Importantly, we observed an interaction between STAT3 and IQ motif-containing GTPase-activating protein 1 (IQGAP1), a scaffolding platform that binds CDC42. STAT3 colocalized with CDC42 and IQGAP1 at the plasma membrane, suggesting cross-talk between IL-6-mediated STAT3 signaling and CDC42 activation. These results suggest that IL-6 promotes metastatic invasion, at least partially, through CDC42 and that, along with its pleiotropic effects on tumor growth and progression, IL-6 signaling also activates proinvasive GTPase signaling, priming tumor cells for metastatic invasion.

A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma

“…[44] Besides, fibrin is also reported in the PDAC tissue, which is associated with thrombin-mediated proteolysis of fibrinogen. [59] Second, although only TGF-β1 was tested in the present study, the present model can be used to test the effects of various growth factors and their combinations on the EMT and local invasion of cancer cells including IL-6 [60] and EGF. [61] In addition, for broader applications, it would be desired to have an in vitro model of normal epithelial duct.…”

Stroma secreted IL6 selects for “stem-like” population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways

“…IL6 has been shown to be involved in progression of pancreatic tumors by others 16, 36, 37, 38, 39 . Furthermore, in pancreatic cancer patient population, increased expression of IL6 correlated with poor survival (Figure 6A).…”

Identification of Prognosis-Related Genes and Construction of Multi-regulatory Networks in Pancreatic Cancer Microenvironment by Bioinformatics Analysis

“…For instance, WSPAR has been reported to promote hepatocellular carcinoma aggressiveness through epithelial-mesenchymal transition (52). It is worth mentioning that the IL-6 produced by non-neoplastic components within pancreatic tumors could activate proin ammatory STAT3 signaling in hepatocytes (53). In turn, by enhancing hepatic stellate cell activation, those hepatocytes release myeloid cell chemoattractant proteins to recruit myeloid cells and increase brosis deposition (54).…”