OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy 
and lacks effective treatment. We aimed to understand molecular mechanisms of 
the intertwined interactions between tumour stromal components in metastasis and 
to provide a new paradigm for PDAC therapy.
DESIGN: Two unselected cohorts of 154 and 20 patients with PDAC were subjected 
to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. 
Unbiased expression profiling, and genetic and pharmacological gain-of-function 
and loss-of-function approaches were employed to identify molecular signalling 
in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated 
fibroblasts (myoCAFs). The role of the IL-33-ST2-CXCL3-CXCR2 axis in PDAC 
metastasis was evaluated in three clinically relevant mouse PDAC models.
RESULTS: IL-33 was specifically elevated in human PDACs and positively 
correlated with tumour inflammation in human patients with PDAC. CXCL3 was 
highly upregulated in IL-33-stimulated macrophages that were the primary source 
of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. 
Mechanistically, activation of the IL-33-ST2-MYC pathway attributed to high 
CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other 
cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. 
Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth 
muscle actin (α-SMA) was uniquely upregulated by the CXCL3-CXCR2 signalling. 
Type III collagen was identified as the CXCL3-CXCR2-targeted adhesive molecule 
responsible for myoCAF-driven PDAC metastasis.
CONCLUSIONS: Our work provides novel mechanistic insights into understanding 
PDAC metastasis by the TAM-CAF interaction and targeting each of these 
signalling components would provide an attractive and new paradigm for treating 
pancreatic cancer.