A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy.

We identified neuronal pentraxin 1 (NPTX1) as a cancer-secreted protein that becomes overexpressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig-like domain 2 (AMIGO2) as its receptor.

Molecular, genetic, biochemical, and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis.

NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia-inducible factor-1α (HIF1α) nuclear retention and function. NPTX1 is overexpressed in human PDAC tumors and upregulated in liver metastases.

Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1α hypoxic response in PDAC.

Significance: We identified the NPTX1-AMIGO2 axis as a regulatory mechanism upstream of HIF1α-driven hypoxia response that promotes PDAC liver metastasis.

Therapeutic NPTX1 targeting outperformed a common chemotherapy regimen in inhibiting liver metastasis and suppressed primary tumor growth in preclinical models, revealing a novel therapeutic strategy targeting hypoxic response in PDAC.

References:

Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74(1):12–49 doi 10.3322/caac.21820.
Stoffel EM, Brand RE, Goggins M. Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention. Gastroenterology 2023;164(5):752–65 doi 10.1053/j.gastro.2023.02.012.
Yang A, Herter-Sprie G, Zhang H, Lin EY, Biancur D, Wang X, et al. Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms. Cancer Discov 2018;8(3):276–87 doi 10.1158/2159-8290.CD-17-0952.
Zhu XG, Chudnovskiy A, Baudrier L, Prizer B, Liu Y, Ostendorf BN, et al. Functional Genomics In Vivo Reveal Metabolic Dependencies of Pancreatic Cancer Cells. Cell Metab 2021;33(1):211–21 e6 doi 10.1016/j.cmet.2020.10.017.
Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 2015;524(7565):361–5 doi 10.1038/nature14587.

Article info

Journal issue:

Volume: 14
Issue: 12

Doi:

10.1158/2159-8290.CD-23-1323

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A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy.

Significance: We identified the NPTX1-AMIGO2 axis as a regulatory mechanism upstream of HIF1α-driven hypoxia response that promotes PDAC liver metastasis.

References:

Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74(1):12–49 doi 10.3322/caac.21820.
Stoffel EM, Brand RE, Goggins M. Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention. Gastroenterology 2023;164(5):752–65 doi 10.1053/j.gastro.2023.02.012.
Yang A, Herter-Sprie G, Zhang H, Lin EY, Biancur D, Wang X, et al. Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms. Cancer Discov 2018;8(3):276–87 doi 10.1158/2159-8290.CD-17-0952.
Zhu XG, Chudnovskiy A, Baudrier L, Prizer B, Liu Y, Ostendorf BN, et al. Functional Genomics In Vivo Reveal Metabolic Dependencies of Pancreatic Cancer Cells. Cell Metab 2021;33(1):211–21 e6 doi 10.1016/j.cmet.2020.10.017.
Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 2015;524(7565):361–5 doi 10.1038/nature14587.