A targetable secreted neural protein drives pancreatic cancer metastatic colonization and HIF1a nuclear retention.
Norihiro YamaguchiY Gloria WuEthan RavetchMai TakahashiAbdul G KhanAkimasa HayashiWenbin MeiDennis J HsuShigeaki UmedaElisa De StanchinaIvo C LorenzChristine A Iacobuzio-DonahueSohail F TavazoiePublished in: Cancer discovery (2024)
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 over-expressed 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 induced factor-1a (HIF1a) nuclear retention and function. NPTX1 is over-expressed 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 HIF1a hypoxic response in PDAC.
Keyphrases
- endothelial cells
- squamous cell carcinoma
- small cell lung cancer
- monoclonal antibody
- papillary thyroid
- liver metastases
- single cell
- squamous cell
- induced apoptosis
- pluripotent stem cells
- palliative care
- induced pluripotent stem cells
- stem cells
- cell therapy
- protein protein
- amino acid
- drug delivery
- small molecule
- transcription factor
- cell proliferation
- radiation therapy
- cystic fibrosis
- brain injury
- mesenchymal stem cells
- cell death
- signaling pathway
- locally advanced
- staphylococcus aureus
- endoplasmic reticulum stress
- subarachnoid hemorrhage