Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis

Kosuke Ogawa; Qiushi Lin; Le Li; Xuewei Bai; Xuesong Chen; Hua Chen; Rui Kong; Yongwei Wang; Hong Zhu; Fuliang He; Qinggang Xu; Lianxin Liu; Min Li; Songhua Zhang; Katsuya Nagaoka; Rolf Carlson; Howard Safran; Kevin Charpentier; Bei Sun; Jack Wands; Xiaoqun Dong

doi:10.1016/j.canlet.2020.02.039

Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis

Kosuke Ogawa, Qiushi Lin, Le Li, Xuewei Bai, Xuesong Chen, Hua Chen, Rui Kong, Yongwei Wang, Hong Zhu, Fuliang He, Qinggang Xu, Lianxin Liu, Min Li, Songhua Zhang, Katsuya Nagaoka, Rolf Carlson, Howard Safran, Kevin Charpentier, Bei Sun, Jack WandsXiaoqun Dong

Houston Methodist

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

To demonstrate multifaceted contribution of aspartate β-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's β-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.

Original language	English (US)
Pages (from-to)	63-75
Number of pages	13
Journal	Cancer Letters
Volume	481
DOIs	https://doi.org/10.1016/j.canlet.2020.02.039
State	Published - Jul 1 2020

Keywords

Aspartate β-hydroxylase (ASPH)
Exosome
Notch
Pancreatic ductal adenocarcinoma (PDAC)
Patient derived xenograft (PDX)
Small molecule inhibitor (SMI)

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2020.02.039

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Ogawa, K., Lin, Q., Li, L., Bai, X., Chen, X., Chen, H., Kong, R., Wang, Y., Zhu, H., He, F., Xu, Q., Liu, L., Li, M., Zhang, S., Nagaoka, K., Carlson, R., Safran, H., Charpentier, K., Sun, B., ... Dong, X. (2020). Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis. Cancer Letters, 481, 63-75. https://doi.org/10.1016/j.canlet.2020.02.039

Ogawa, K, Lin, Q, Li, L, Bai, X, Chen, X, Chen, H, Kong, R, Wang, Y, Zhu, H, He, F, Xu, Q, Liu, L, Li, M, Zhang, S, Nagaoka, K, Carlson, R, Safran, H, Charpentier, K, Sun, B, Wands, J & Dong, X 2020, 'Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis', Cancer Letters, vol. 481, pp. 63-75. https://doi.org/10.1016/j.canlet.2020.02.039

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title = "Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis",

abstract = "To demonstrate multifaceted contribution of aspartate β-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's β-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.",

keywords = "Aspartate β-hydroxylase (ASPH), Exosome, Notch, Pancreatic ductal adenocarcinoma (PDAC), Patient derived xenograft (PDX), Small molecule inhibitor (SMI)",

author = "Kosuke Ogawa and Qiushi Lin and Le Li and Xuewei Bai and Xuesong Chen and Hua Chen and Rui Kong and Yongwei Wang and Hong Zhu and Fuliang He and Qinggang Xu and Lianxin Liu and Min Li and Songhua Zhang and Katsuya Nagaoka and Rolf Carlson and Howard Safran and Kevin Charpentier and Bei Sun and Jack Wands and Xiaoqun Dong",

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year = "2020",

month = jul,

day = "1",

doi = "10.1016/j.canlet.2020.02.039",

language = "English (US)",

volume = "481",

pages = "63--75",

journal = "Cancer Letters",

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TY - JOUR

T1 - Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis

AU - Ogawa, Kosuke

AU - Lin, Qiushi

AU - Li, Le

AU - Bai, Xuewei

AU - Chen, Xuesong

AU - Chen, Hua

AU - Kong, Rui

AU - Wang, Yongwei

AU - Zhu, Hong

AU - He, Fuliang

AU - Xu, Qinggang

AU - Liu, Lianxin

AU - Li, Min

AU - Zhang, Songhua

AU - Nagaoka, Katsuya

AU - Carlson, Rolf

AU - Safran, Howard

AU - Charpentier, Kevin

AU - Sun, Bei

AU - Wands, Jack

AU - Dong, Xiaoqun

PY - 2020/7/1

Y1 - 2020/7/1

N2 - To demonstrate multifaceted contribution of aspartate β-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's β-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.

AB - To demonstrate multifaceted contribution of aspartate β-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's β-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.

KW - Aspartate β-hydroxylase (ASPH)

KW - Exosome

KW - Notch

KW - Pancreatic ductal adenocarcinoma (PDAC)

KW - Patient derived xenograft (PDX)

KW - Small molecule inhibitor (SMI)

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DO - 10.1016/j.canlet.2020.02.039

M3 - Article

C2 - 32145343

AN - SCOPUS:85083047682

SN - 0304-3835

VL - 481

SP - 63

EP - 75

JO - Cancer Letters

JF - Cancer Letters

ER -

Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis

Abstract

Keywords

ASJC Scopus subject areas

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