Molecular mechanisms of IL-33–mediated stromal interactions in cancer metastasis
Patrik Andersson, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, Guohua Yu, Shihai Liu, Rudi Beyaert, Mayland Chang, Qi Li, Yihai Cao
Patrik Andersson, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, Guohua Yu, Shihai Liu, Rudi Beyaert, Mayland Chang, Qi Li, Yihai Cao
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Research Article Cell biology Oncology

Molecular mechanisms of IL-33–mediated stromal interactions in cancer metastasis

Abstract

Molecular mechanisms underlying the cancer stroma in metastasis need further exploration. Here, we discovered that cancer-associated fibroblasts (CAFs) produced high levels of IL-33 that acted on tumor-associated macrophages (TAMs), causing them to undergo the M1 to M2 transition. Genomic profiling of metastasis-related genes in the IL-33–stimulated TAMs showed a >200-fold increase of MMP9. Signaling analysis demonstrated the IL-33-ST2-NF-κB-MMP9-laminin pathway that governed tumor stroma–mediated metastasis. In mouse and human fibroblast-rich pancreatic cancers, genetic deletion of IL-33, ST2, or MMP9 markedly blocked metastasis. Pharmacological inhibition of NF-κB and MMP9 also blocked cancer metastasis. Deletion of IL-33, ST2, or MMP9 restored laminin, a key basement membrane component associated with tumor microvessels. Together, our data provide mechanistic insights on the IL-33-NF-κB-MMP9-laminin axis that mediates the CAF-TAM–committed cancer metastasis. Thus, targeting the CAF-TAM-vessel axis provides an outstanding therapeutic opportunity for cancer treatment.

Authors

Patrik Andersson, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, Guohua Yu, Shihai Liu, Rudi Beyaert, Mayland Chang, Qi Li, Yihai Cao

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Figure 5

Activation of IL-33-ST2-NF-κB-MMP9 signaling promotes metastasis.

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Activation of IL-33-ST2-NF-κB-MMP9 signaling promotes metastasis. (A) Vi...
(A) Visible surface pulmonary metastatic nodules and lung histology of Panc02 tumor-bearing WT, Il33–/–, or St2–/– mice. Arrowheads indicate lung surface metastatic nodules. Dashed line marks the border between the metastatic nodule (T) and surrounding lung tissues (L) (scale bar: 250 μm). Quantification of the percentage of animals with visible pulmonary metastasis (n = 6–10 mice per group). (B) Visible surface pulmonary metastatic nodules and lung histology of Panc02 tumor-bearing mice receiving vehicle or soluble ST2 (sST2) treatments. Arrowheads indicate lung surface metastatic nodules. Dashed line marks the border between the metastatic nodule and surrounding lung tissues (scale bar: 250 μm). Quantification of the percentage of animals with visible pulmonary metastasis (n = 6–10 mice per group). (C) Visible surface pulmonary metastatic nodules and lung histology of Panc02 tumor-bearing mice receiving PBS or clodronate treatments. Arrowheads indicate lung surface metastatic nodules. Dashed line marks the border between the metastatic nodule and surrounding lung tissues (scale bar: 250 μm). Quantification of the percentage of animals with visible pulmonary metastasis (n = 6–10 mice per group). (D) Visible surface pulmonary metastatic nodules and lung histology of Panc02 tumor-bearing mice receiving vehicle or DHMEQ (a NF-κB inhibitor) treatments. Arrowheads indicate lung surface metastatic nodules. Dashed line marks the border between the metastatic nodule and surrounding lung tissues (scale bar: 250 μm). Quantification of the percentage of animals with visible pulmonary metastasis (n = 6–10 mice per group). (E) Visible surface pulmonary metastatic nodules and lung histology of Panc02 tumor-bearing mice receiving vehicle or SB-3CT (a MMP9 inhibitor) treatments. Arrowheads indicate lung surface metastatic nodules. Dashed line marks the border between the metastatic nodule and surrounding lung tissues (scale bar: 250 μm). Quantification of the percentage of animals with visible pulmonary metastasis (n = 6–10 mice per group). (F) Visible surface pulmonary metastatic nodules and lung histology of Panc02 tumor-bearing WT or Mmp9–/– mice. Arrowheads indicate lung surface metastatic nodules. Dashed line marks the border between the metastatic nodule and surrounding lung tissues (scale bar: 250 μm). Quantification of percentage of animals with visible pulmonary metastasis (n = 6–10 mice per group).