Dan Su

Peking Union Medical College Hospital

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Guihu Weng

Chinese Academy of Medical Sciences & Peking Union Medical College

Jinxin Tao

Chinese Academy of Medical Sciences & Peking Union Medical College

Gang Yang

Gansu Agricultural University

Wenhao Luo

Peking Union Medical College Hospital

Jiangdong Qiu

Chinese Academy of Medical Sciences & Peking Union Medical College

Yuanyang Wang

Zhejiang Center for Disease Control and Prevention

Yueze Liu

Peking Union Medical College Hospital

Guangyu Chen

Hunan University of Traditional Chinese Medicine

Taiping Zhang

Peking Union Medical College Hospital

Chen Ding

Chinese Academy of Medical Sciences & Peking Union Medical College

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Chinese Academy of Medical Sciences & Peking Union Medical College

Peking Union Medical College Hospital

Shanghai Jiao Tong University

Academy of Medical Sciences

Chinese Academy of Sciences

Nanjing Medical University

Zhengzhou University

University of Chinese Academy of Sciences

Tumor Hospital of Guangxi Medical University

Committee on Publication Ethics

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Data from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis

Dan Su Ruobing Wang Guangyu Chen Chen Ding Yueze Liu

<div>AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide, primarily due to its rapid progression. The current treatment options for PDAC are limited, and a better understanding of the underlying mechanisms responsible for PDAC progression is required to identify improved therapeutic strategies. In this study, we identified FBXO32 as an oncogenic driver in PDAC. FBXO32 was aberrantly upregulated in PDAC, and high FBXO32 expression was significantly associated with an unfavorable prognosis in patients with PDAC. FRG1 deficiency promoted FBXO32 upregulation in PDAC. FBXO32 promoted cell migration and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, FBXO32 directly interacted with eEF1A1 and promoted its polyubiquitination at the K273 site, leading to enhanced activity of eEF1A1 and increased protein synthesis in PDAC cells. Moreover, FBXO32-catalyzed eEF1A1 ubiquitination boosted the translation of ITGB5 mRNA and activated focal adhesion kinase (FAK) signaling, thereby facilitating focal adhesion assembly and driving PDAC progression. Importantly, interfering with the FBXO32–eEF1A1 axis or pharmaceutical inhibition of FAK by defactinib, an FDA-approved FAK inhibitor, substantially inhibited PDAC growth and metastasis driven by aberrantly activated FBXO32–eEF1A1 signaling. Overall, this study uncovers a mechanism by which PDAC cells rely on FBXO32-mediated eEF1A1 activation to drive progression and metastasis. FBXO32 may serve as a promising biomarker for selecting eligible patients with PDAC for treatment with defactinib.Significance: FBXO32 upregulation in pancreatic cancer induced by FRG1 deficiency increases eEF1A1 activity to promote ITGB5 translation and stimulate FAK signaling, driving cancer progression and sensitizing tumors to the FAK inhibitor defactinib.</div>

Tumor progression

10.1158/0008-5472.c.7403518.v1

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Supplementary Fig. S24 from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis

Dan Su Ruobing Wang Guangyu Chen Chen Ding Yueze Liu

Supplementary Fig. S24

10.1158/0008-5472.26711185.v1

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Supplementary Fig. S18 from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis

Dan Su Ruobing Wang Guangyu Chen Chen Ding Yueze Liu

Supplementary Fig. S18

10.1158/0008-5472.26711212

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Supplementary Fig. S17 from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis

Dan Su Ruobing Wang Guangyu Chen Chen Ding Yueze Liu

Supplementary Fig. S17

10.1158/0008-5472.26711215.v1

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Supplementary Fig. S18 from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis

Dan Su Ruobing Wang Guangyu Chen Chen Ding Yueze Liu

Supplementary Fig. S18

10.1158/0008-5472.26711212.v1

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Supplementary Fig. S14 from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis

Dan Su Ruobing Wang Guangyu Chen Chen Ding Yueze Liu

Supplementary Fig. S14

10.1158/0008-5472.26711227.v1

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The diagnostic value of 1.5-T diffusion-weighted MR imaging in detecting 5 to 10 mm metastatic cervical lymph nodes of nasopharyngeal carcinoma

Medicine (2016)

Guan Jin Jun Yang Li Dong Liu Dan Su Duo Ping Wang

The aim of the study was to prospectively assess the diagnostic accuracy of 1.5 T diffusion-weighted imaging (DWI) for 5 to 10 mm metastatic cervical lymph nodes of patients with nasopharyngeal carcinoma (NPC). All patients with histopathologically confirmed NPC underwent DWI with 2 b values of 0 and 800 s/mm2 were enrolled. The shortest axial diameter and mean apparent diffusion coefficient (ADC) value were recorded when lymph nodes with a shortest axial diameter from 5 to 10 mm were measured. The correlation between the pathological diagnoses and mean ADC values in the benign and metastatic lymph nodes were compared using the Z test. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of DWI. Three hundred fourteen nodes of 52 patients with NPC consisted of 46.5% (146/314) metastatic lymph nodes and 53.5% (168/314) benign lymph nodes. The mean ADC value (×10–3 mm2/s) of benign lymph nodes was (1.110 ± 0.202), which was significantly higher than that of metastatic nodes (0.878 ± 0.159) (P < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value, accuracy for differentiating metastatic from benign lymph nodes using a cutoff ADC value of 0.924 × 10–3 mm2/s was 83.56%, 82.74%, 80.79%, 85.28%, and 82.80%, respectively. The area under the ROC curve was 0.851 (95% confidence intervals: 0.807–0.889). This study demonstrated that DWI is helpful in detecting 5 to 10 mm metastatic lymph nodes of patients with NPC.

Cervical lymph nodes

10.1097/md.0000000000004286

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Supplementary Fig. S26 from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis

Dan Su Ruobing Wang Guangyu Chen Chen Ding Yueze Liu

Supplementary Fig. S26

10.1158/0008-5472.26711179.v1

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Supplementary Fig. S15 from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis

Dan Su Ruobing Wang Guangyu Chen Chen Ding Yueze Liu