Autotaxin–lysolipid signaling suppresses a CCL11–eosinophil axis to promote pancreatic cancer progression Journal Article

   

Authors:	Bhattacharyya, S.; Oon, C.; Diaz, L.; Sandborg, H.; Stempinski, E. S.; Saoi, M.; Morgan, T. K.; López, C. S.; Cross, J. R.; Sherman, M. H.
Article Title:	Autotaxin–lysolipid signaling suppresses a CCL11–eosinophil axis to promote pancreatic cancer progression
Abstract:	Lipids and their modifying enzymes regulate diverse features of the tumor microenvironment and cancer progression. The secreted enzyme autotaxin (ATX) hydrolyzes extracellular lysophosphatidylcholine to generate the multifunctional lipid mediator lysophosphatidic acid (LPA) and supports the growth of several tumor types, including pancreatic ductal adenocarcinoma (PDAC). Here we show that ATX suppresses the accumulation of eosinophils in the PDAC microenvironment. Genetic or pharmacologic ATX inhibition increased the number of intratumor eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop, wherein ATX–LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, in turn suppressing the expression of the potent eosinophil chemoattractant CCL11 (eotaxin-1). Eosinophils were identified in human PDAC specimens, and rare individuals with high intratumor eosinophil abundance had the longest overall survival. Together with recent findings, this study reveals the context-dependent, immune-modulatory potential of ATX–LPA signaling in cancer. © The Author(s) 2024.
Keywords:	immunohistochemistry; signal transduction; controlled study; human tissue; allograft; human cell; genetics; nonhuman; pancreas cancer; pancreatic neoplasms; flow cytometry; mouse; metabolism; animal tissue; apoptosis; gene expression; confocal microscopy; image analysis; eotaxin; carcinoma, pancreatic ductal; animal experiment; animal model; enzyme linked immunosorbent assay; fluorescence in situ hybridization; chromatin immunoprecipitation; echography; pancreas tumor; western blotting; plasmid; pancreas adenocarcinoma; real time polymerase chain reaction; physical examination; tissue microarray; oncogenesis and malignant transformation; neoplastic processes; histogram; tumor microenvironment; image segmentation; transmission electron microscopy; eosinophil; eosinophils; pancreatic ductal carcinoma; lysophosphatidylcholine; lysophosphatidylcholines; orthotopic transplantation; autotaxin; lysophosphatidic acid; humans; human; male; female; article; cell viability assay; giemsa stain; immunofluorescence assay; tunel assay; sandwich elisa; chemokine ccl11; chemokine receptor ccr3 antagonist; ccl11 protein, human; autotaxin lysolipid signaling; patu 8988t cell line
Journal Title:	Nature Cancer
Volume:	5
Issue:	2
ISSN:	2662-1347
Publisher:	Nature Research
Date Published:	2024-02-01
Start Page:	283
End Page:	298
Language:	English
DOI:	10.1038/s43018-023-00703-y
PUBMED:	38195933
PROVIDER:	scopus
PMCID:	PMC10899115
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85181917927&doi=10.1038%2fs43018-023-00703-y&partnerID=40&md5=4060ffbad6505a6cb2497d27de64105d
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Mara H. Sherman -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/214880