{"doi":"10.1158/2159-8290.cd-23-1323","title":"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.","journal":"Cancer Discovery","year":2024,"id":428628,"datarank":0.46787472091879556,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.08313231729956502,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.08313231729956502,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":12,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1230750,"name":"Y. Gloria Wu","orcid":null,"position":1,"is_corresponding":false},{"id":1230233,"name":"Ethan Ravetch","orcid":"0000-0002-8891-6296","position":2,"is_corresponding":false},{"id":1230234,"name":"M Takahashi","orcid":"0000-0001-6015-6291","position":3,"is_corresponding":false},{"id":697278,"name":"Abdul G. Khan","orcid":null,"position":4,"is_corresponding":false},{"id":266131,"name":"Akimasa Hayashi","orcid":"0000-0002-7424-8127","position":5,"is_corresponding":false},{"id":848138,"name":"Wenbin Mei","orcid":"0000-0001-9906-0916","position":6,"is_corresponding":false},{"id":1179554,"name":"Dennis Hsu","orcid":"0000-0003-4200-1098","position":7,"is_corresponding":false},{"id":873707,"name":"Shigeaki Umeda","orcid":"0000-0001-5693-1515","position":8,"is_corresponding":false},{"id":225995,"name":"Elisa de Stanchina","orcid":"0000-0002-3873-315X","position":9,"is_corresponding":false},{"id":477729,"name":"Ivo C. Lorenz","orcid":"0000-0002-7373-1176","position":10,"is_corresponding":false},{"id":14372,"name":"Christine A. Iacobuzio–Donahue","orcid":"0000-0002-4672-3023","position":11,"is_corresponding":false},{"id":258953,"name":"Sohail F. Tavazoie","orcid":"0000-0002-4966-9018","position":12,"is_corresponding":false},{"id":266894,"name":"Norihiro Yamaguchi","orcid":"0000-0001-8023-9748","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:59:02.165535Z","pmid":"39028915","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}