A targetable secreted neural protein drives pancreatic cancer metastatic colonization and HIF1α nuclear retention Journal Article

   

Authors:	Yamaguchi, N.; Wu, Y. G.; Ravetch, E.; Takahashi, M.; Khan, A. G.; Hayashi, A.; Mei, W.; Hsu, D.; Umeda, S.; de Stanchina, E.; Lorenz, I. C.; Iacobuzio-Donahue, C. A.; Tavazoie, S. F.
Article 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 anti-body 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. © 2024 American Association for Cancer Research.
Keywords:	immunohistochemistry; controlled study; human tissue; protein expression; unclassified drug; human cell; gene deletion; splenectomy; cancer growth; nonhuman; liver neoplasms; gemcitabine; pancreas cancer; pancreatic neoplasms; pancreaticoduodenectomy; cell proliferation; c reactive protein; animal cell; mouse; animal; metabolism; animals; mice; cell viability; gene; gene overexpression; metastasis; apoptosis; gene expression; carcinoma, pancreatic ductal; animal experiment; animal model; nerve tissue proteins; c-reactive protein; immunofluorescence; pathology; cell line, tumor; angiogenesis; proteomics; enzyme linked immunosorbent assay; histology; cancer mortality; hypoxia; ubiquitination; genetic transfection; liver tumor; escherichia coli; pancreas tumor; tumor cell line; western blotting; scoring system; neoplasm metastasis; immunoprecipitation; pimonidazole; eosin; hematoxylin; dye; tumor growth; autopsy; drug therapy; doxycycline; ubiquitin protein ligase e3; tetracycline; hypoxia inducible factor 1alpha; nerve protein; fluorescence activated cell sorting; cell invasion; bioluminescence; phage display; rank sum test; student t test; hif1a protein, human; hypoxia-inducible factor 1, alpha subunit; stoichiometry; immunization; tumor microenvironment; saponin; short tandem repeat; glucose metabolism; pancreatic ductal carcinoma; metastatic progression; metastatic colonization; genomic copy number; tumor spheroid; humans; human; article; rna sequencing; cell growth assay; differential expression analysis; polyvinylidene fluoride; 4',6 diamidino 2 phenylindole; transwell assay; adhesion molecule with ig like domain 2; neuronal pentraxin 1; neuronal pentraxin; anc1 lm3 cell; burkholderia pseudomallei; hypoxia cell growth assay; in vivo crispr competition assay; in vivo devd luciferase apoptosis assay; in vivo hypoxia pimonidazole reporter assay; in vivo spontaneous metastasis assay; ki 67 immunofluorescence staining; kpc lm2 cell; liver metastasis assay; luciferin based apoptosis assay; mantel cox log rank test; mia paca-2 cell; mst assay; neuronal cell death; nuclear retention; orthotopic liver metastatic progression capacity; proximity ligation assay; stable cell line
Journal Title:	Cancer Discovery
Volume:	14
Issue:	12
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2024-12-01
Start Page:	2489
End Page:	2508
Language:	English
DOI:	10.1158/2159-8290.Cd-23-1323
PUBMED:	39028915
PROVIDER:	scopus
PMCID:	PMC11611693
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85211472773&doi=10.1158%2f2159-8290.CD-23-1323&partnerID=40&md5=d6c659f775e7eaca63a7fcecb5ce516b
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/221138