Abstract
Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that higher levels of cytoplasmic leukemia inhibitory factor (LIF) and LIF receptor are correlated with poorer metastasis/recurrence-free survival. Further, single nucleotide variations and signal peptide mutation of LIF are identified in NPC. Cytoplasmic LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically through modulation of YAP1-FAK/PXN signaling. Immunohistochemical analyses of NPC biopsies reveal a positive correlation of cytoplasmic LIF expression with focal adhesion kinases. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer dissemination, targeting of this pathway presents a promising opportunity to block metastasis.
Highlights
Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma
Immunohistochemical results exhibited strong immunoreactivity of cytoplasmic leukemia inhibitory factor (LIF) in primary tumors obtained from nasopharyngeal carcinoma (NPC) patients diagnosed with local recurrence or distal metastasis, which was even stronger in metastatic tumor lesions (Fig. 1b), those metastasizing to liver or lung (Fig. 1b, right)
Multivariate Cox regression analyses indicated that higher cytoplasmic LIF expression is an independent prognostic factor for lower metastasis-free survival [p = 0.047; hazard ratio = 1.873, 95% confidence interval (CI) = 1.007–3.482] and lower local recurrence-free survival [p = 0.043; hazard ratio = 1.838, 95% CI = 1.019–3.315] (Supplementary Table 2)
Summary
Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that higher levels of cytoplasmic leukemia inhibitory factor (LIF) and LIF receptor are correlated with poorer metastasis/recurrence-free survival. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically through modulation of YAP1-FAK/PXN signaling. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Several invadopodia-promoting growth factors, such as EGF, TGF-β, heparin binding (HB)-EGF, VEGF, and HGF, converge on signaling involving Src kinase, PI3K and Rho family GTPases, which control formation of invadopodia[15,19]. Pharmacological blockade of these upstream regulators of invadopodia presents a promising strategy to prevent metastasis. Our data support the therapeutic efficacy of AZD0530 (saracatinib) in suppressing vascular dissemination and local invasion in nasopharyngeal carcinoma (NPC)
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