A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention
Norihiro Yamaguchi, Y. Gloria Wu, Ethan Ravetch, M Takahashi, Abdul G. Khan, Akimasa Hayashi, Wenbin Mei, Dennis Hsu, Shigeaki Umeda, Elisa de Stanchina, Ivo C. Lorenz, Christine A. Iacobuzio–Donahue, Sohail F. Tavazoie
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.