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

Abstract

ObjectivePancreatic 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.DesignTwo 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.ResultsIL-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.ConclusionsOur 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.

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

“…In a recent study, Sun et al reported that CXCL3 was highly upregulated in IL-33-stimulated macrophages and the receptor of CXCL3 (CXCR2) was mostly expressed by CAFs (341). In addition, CXCL3-CXCR2 signaling upregulated a-SMA and activation of CXCR2 by CXCL3 caused CAF-to-myoCAF transition (341). These findings underline the importance of the interaction between CAFs and immune cells in terms of generating a favorable inflammatory niche in breast cancer lung metastasis.…”

“…in vivo IL-33 targeting caused inhibition of lung metastasis and significant reduction of immune cell recruitment (340). In a recent study, Sun et al reported that CXCL3 was highly upregulated in IL-33-stimulated macrophages and the receptor of CXCL3 (CXCR2) was mostly expressed by CAFs (341). In addition, CXCL3-CXCR2 signaling upregulated a-SMA and activation of CXCR2 by CXCL3 caused CAF-to-myoCAF transition (341).…”

The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

“…CAFs also express regulatory molecules, such as growth factors that affect tumor angiogenesis, and participate in the activation of quiescent fibroblasts [50][51][52], chemokines generating an immunosuppressive TME [53], and cytokines inducing inflammation [41,54]. All of these characteristics make CAFs a real "cellular conductor" that truly controls tumor growth in the primary tumor and metastases [55][56][57], also playing a role in the acquisition of drug resistance [58][59][60][61]. The protumorigenic potential of CAFs has prompted studies to target this cell type as a therapy for the PDAC.…”

Clinical significance and biological functions of chemokine CXCL3 in head and neck squamous cell carcinoma

“…According to the arrangement of the amino-terminal (N-terminal) cysteines (Cys), chemokines are divided into different subfamilies: CXC Downloaded from http://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20212403/925605/bsr-2021-2403.pdf by guest on 13 December 2021 (α), CC (β), CX3C (γ) and C (δ) [5]. In recent years, a growing number of studies indicated that CXC chemokine ligand (CXCL) 3 is constitutively expressed in several tumor types, and its high-level expression is extremely related to the advanced-stage, high-grade and lymph node metastasis [6]. For example, it has been suggested that that CXCL3 was highly expressed in prostate cancer and high CXCL3 expression was closely related to the poor prognosis of patients [7].…”