2. Academic Validation
  3. Autotaxin-lysolipid signaling suppresses a CCL11-eosinophil axis to promote pancreatic cancer progression

Autotaxin-lysolipid signaling suppresses a CCL11-eosinophil axis to promote pancreatic cancer progression

  • Nat Cancer. 2024 Jan 9. doi: 10.1038/s43018-023-00703-y.
Sohinee Bhattacharyya 1 2,  Chet Oon 1 2,  Luis Diaz 1,  Holly Sandborg 1 2,  Erin S Stempinski 3,  Michelle Saoi 4,  Terry K Morgan 5,  Claudia S López 3 6,  Justin R Cross 4,  Mara H Sherman 7 8
Affiliations

Affiliations

  • 1 Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
  • 2 Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Multiscale Microscopy Core Facility, Oregon Health & Science University, Portland, OR, USA.
  • 4 Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 5 Department of Pathology, Oregon Health & Science University, Portland, OR, USA.
  • 6 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA.
  • 7 Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA. shermam1@mskcc.org.
  • 8 Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. shermam1@mskcc.org.
PMID: 38195933 DOI: 10.1038/s43018-023-00703-y
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.

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