BackgroundAspartate β-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer.MethodsStable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied.ResultsThrough physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH’s β-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis.ConclusionsASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH’s pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.

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Background This real‐world study assessed the efficacy and toxicity of anlotinib as salvage treatment in Chinese patients with advanced non‐small cell lung cancer (NSCLC). Methods The medical records of 81 patients with advanced NSCLC who had failed at least two lines of chemotherapy were retrospectively collected. All patients were administered anlotinib treatment until disease progression or intolerance as a result of adverse events. Survival curves were created using the Kaplan–Meier method. The log‐rank test was used for univariate analysis of progression‐free survival (PFS) between groups. Cox regression was used to estimate the statistically significant factors based on univariate analysis. Results The median PFS was five months (95% confidence interval [CI] 3.5–6.5). The objective response rate (ORR) was 7% and the disease control rate (DCR) was 84%. The following subgroups of patients had longer PFS (P < 0.05): squamous cell carcinoma, no brain or liver metastases, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, and no previous VEGF‐tyrosine kinase inhibitor treatment. The results of Cox regression indicated that an ECOG PS of 0–1 (hazard ratio 0.152, 95% CI 0.057–0.403; P = 0.00) and patients without brain metastases (hazard ratio 0.421, 95% CI 0.195–0.911; P = 0.028) had longer PFS following anlotinib treatment. Conclusion Anlotinib, which is well tolerated, plays a significant role in the salvage treatment of advanced NSCLC. Patients with advanced NSCLC with an ECOG PS of 0–1 and no brain metastases achieved longer PFS following anlotinib salvage treatment.