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http://purl.uniprot.org/citations/31888763http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/31888763http://www.w3.org/2000/01/rdf-schema#comment"

Background

Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate β-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis.

Methods

To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH's β-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models.

Results

ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0-2 (n = 4), 3-5 (n = 8), 6-8 (n = 24), and 9-12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001).

Conclusion

Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.org/dc/terms/identifier"doi:10.1186/s13045-019-0837-z"xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Chen X."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Chen H."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Dong X."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"He F."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Li L."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Lin Q."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Li M."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Liu L."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Ogawa K."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Sun B."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Wang Y."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Xu Q."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Zhang S."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Zhu H."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Bai X."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Nagaoka K."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Carlson R."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Kong R."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Wands J."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Safran H."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/author"Charpentier K."xsd:string
http://purl.uniprot.org/citations/31888763http://purl.uniprot.org/core/date"2019"xsd:gYear
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