Gene expression profile of F4/80+ cells isolated from tumors implanted in wild type and St2-/- mouse
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69402 | GEO | 2016/05/03
SECONDARY ACCESSION(S): PRJNA285414
REPOSITORIES: GEO
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Project description: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.
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Project description:Vascular pericytes, an important cellular component, in the tumor microenvironment, are often associated with tumor vasculatures and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte fibroblast transition (designated as PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that the PDGF-BB-PDGFRβ signaling promotes PFT in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB-activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRβ ablate the PDGF-BB-induced PFT. Genetic tracing of pericytes with two independent mouse strains, i.e., TN-AP-CreERT2:R26R-tdTomato and NG2:R26R-tdTomato, shows that PFT cells gains stromal fibroblast and myofibroblast markers in tumors. Importantly, co-implantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells (CTCs) and metastasis. Our findings reveal a novel mechanism of vascular pericytes in PDGF-BB-promoted cancer invasion and metastasis by inducing PFT and thus targeting PFT may offer a new treatment option of cancer metastasis.
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