FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis
Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie
Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie
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Research Article Immunology Oncology

FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis

Abstract

Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalk among various cell compartments in supporting metastasis remains poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here, we report that an elevation of FGF-2 signaling in samples from patients with nasopharyngeal carcinoma (NPC) and xenograft mouse models promoted NPC metastasis. Mechanistically, tumor cell–derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1/AHR signaling. Gain- and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization toward an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposome treatment resulted in a reduction of FGF-2–induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2/FGFR1/pericyte/CXCL14/TAM stromal communication axis in NPC and propose an effective antimetastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2hi tumors.

Authors

Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie

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Figure 4

FGF-2 induces CXCL14 expression in pericytes via FGFR1/ERK/AHR signaling.

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FGF-2 induces CXCL14 expression in pericytes via FGFR1/ERK/AHR signaling...
(A) Heatmap of selected genes by inflammatory cytokine/chemokine profiling of vehicle- and FGF-2–treated primary mouse pericytes (n = 3 samples per group). Arrow points to upregulated Cxcl14 gene. (B) Volcano plot of inflammatory gene profiling of vehicle- and FGF-2–stimulated pericytes (n = 3 samples per group). (C and D) Expression levels of Ccl11 and Cxcl14 in vehicle- and FGF-2–stimulated isolated primary pericytes and MS5 fibroblasts (n = 3 samples per group). (E) qPCR quantification of Cxcl14 mRNA levels in F4/80+ TAMs, NG2+ pericytes, CD31+ endothelial cells, and NG2– population isolated from T241-vector and T241–FGF-2 tumors (n = 3 samples per group). (F) qPCR quantification of Cxcl14 mRNA levels in vehicle- and FGF-2–stimulated pericytes in the presence or absence of FGFR1, FGFR2, and FGFR3 specific inhibitors, and pan-FGFR inhibitor (n = 3 samples per group). (G) After 0, 15, 30 minutes of stimulation, FGF-2 induced phosphorylation of AKT and ERK in pericytes. β-Tubulin marks the loading level in each lane. These experiments were repeated twice. (H) qPCR quantification of Cxcl14 mRNA levels in vehicle- and FGF-2–stimulated pericytes in the presence or absence of MEK1/2, ERK1/2, and AKT specific inhibitors (n = 3 samples per group). (I) Volcano plot of predicted transcription factors which bind to Cxcl14 promoter in genome-wide expression profiling of vehicle- and FGF-2–stimulated pericytes (n = 3 samples per group). (J) qPCR quantification of Cxcl14 mRNA levels in vehicle- and FGF-2–stimulated pericytes in the presence or absence of Control or Ahr-specific siRNA (n = 3 samples per group). (K) ChIP assay of AHR binding to the Cxcl14 gene promoter. Nonimmune IgG and Cxcl14 exon 2 regions served as controls (n = 3 samples per group). (L) Mechanistic diagram of the FGF-2/FGFR1/ERK/AHR/CXCL14 signaling pathway. **P < 0.01, ***P < 0.001 by unpaired 2-tailed Student’s t test (C–E and K) or 1-way ANOVA with Tukey’s multiple-comparison analysis (F, H, and J). Data are presented as mean ± SD.