Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism

ABSTRACT: 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 tumor stromal components in metastasis and to provide a new paradigm for PDAC therapy. Design:Two unselected cohorts of 154 and 20 PDAC patients were subjected to correlation between IL-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain- and loss-of-function approaches were employed to identify molecular signaling in TAMs and myoCAFs. The role of the IL-33-ST2-CXCL3-CXCR2 axis in PDAC metastasis was evaluated in 3 clinically relevant mouse PDAC models and in a zebrafish model. Results: IL-33 was specifically elevated in human PDACs and positively correlated with tumor inflammation in human PDAC patients. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human PDAC patients. 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 a-SMA was uniquely upregulated by the CXCL3-CXCR2 signaling. 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 PDAC23 metastasis by the TAM-CAF interaction and targeting each of these signaling components would provide an attractive and new paradigm for treating pancreatic cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE166263 | GEO | 2021/02/06

REPOSITORIES: GEO