The Role of Autotaxin in Cancer
type: CreativeWork
description: Autotaxin (ATX/ENPP2) is a secreted phospholipase D enzyme that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA is the agonist for at least six G protein coupled receptors whose activation stimulates cell proliferation, survival and migration. Overexpression of ATX and increased levels of LPA have been linked to fibrotic and inflammatory diseases and to several cancers. ATX is a therapeutic target and the ATX inhibitor IOA-289 is currently in Phase 1B clinical trials for the treatment of patients with metastatic pancreatic cancer, in combination with gemcitabine. ENPP2 is overexpressed in both pancreatic adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC). In HCC, ATX is produced by both the tumour microenvironment (TME) and tumour cells and our data show that ATX signalling can drive tumour cell growth in an autocrine manner. In contrast, in PDAC the TME primarily expresses ATX. The cell lines, PANC-1 and MIA PaCa-2 and the cancer associated fibroblast (CAF) derived cell line, 0082T, were used as a model to explore ATX signalling in PDAC. Consistent with publicly available mRNA expression data, 0082T cells, but not the PDAC cancer cells, secrete ATX and its substrate LPC. Conditioned media from 0082T cells increased the growth of both PANC-1 and MIA PaCa-2 cells. Treatment of 0082T CAF cells with IOA-289 during media conditioning reduced PDAC cell growth, without impacting CAF cell numbers. Lipidomic analysis showed IOA-289 and PF8380, another ATX inhibitor, reduce the generation of LPA in 0082T CAF conditioned media. 22:6 LPA was shown to be generated by an ATX independent pathway, and production of 22:6 LPA was upregulated upon ATX inhibition. Additionally, 22:6 LPA accumulates in conditioned media when 0082T, PANC-1 and MIA PaCa-2 cells are present, but species of LPA generated by ATX are specifically degraded (16:0,16:1 18:0,18:1). Cell surface lipid phosphate phosphatases (LPPs) dephosphorylate LPA to produce monoacylglycerol.…
abstract: Autotaxin (ATX/ENPP2) is a secreted phospholipase D enzyme that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA is the agonist for at least six G protein coupled receptors whose activation stimulates cell proliferation, survival and migration. Overexpression of ATX and increased levels of LPA have been linked to fibrotic and inflammatory diseases and to several cancers. ATX is a therapeutic target and the ATX inhibitor IOA-289 is currently in Phase 1B clinical trials for the treatment of patients with metastatic pancreatic cancer, in combination with gemcitabine. ENPP2 is overexpressed in both pancreatic adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC). In HCC, ATX is produced by both the tumour microenvironment (TME) and tumour cells and our data show that ATX signalling can drive tumour cell growth in an autocrine manner. In contrast, in PDAC the TME primarily expresses ATX. The cell lines, PANC-1 and MIA PaCa-2 and the cancer associated fibroblast (CAF) derived cell line, 0082T, were used as a model to explore ATX signalling in PDAC. Consistent with publicly available mRNA expression data, 0082T cells, but not the PDAC cancer cells, secrete ATX and its substrate LPC. Conditioned media from 0082T cells increased the growth of both PANC-1 and MIA PaCa-2 cells. Treatment of 0082T CAF cells with IOA-289 during media conditioning reduced PDAC cell growth, without impacting CAF cell numbers. Lipidomic analysis showed IOA-289 and PF8380, another ATX inhibitor, reduce the generation of LPA in 0082T CAF conditioned media. 22:6 LPA was shown to be generated by an ATX independent pathway, and production of 22:6 LPA was upregulated upon ATX inhibition. Additionally, 22:6 LPA accumulates in conditioned media when 0082T, PANC-1 and MIA PaCa-2 cells are present, but species of LPA generated by ATX are specifically degraded (16:0,16:1 18:0,18:1). Cell surface lipid phosphate phosphatases (LPPs) dephosphorylate LPA to produce monoacylglycerol.…
author: Maggs, Lauren
language: eng
keywords: Autotaxin, CAF, Cancer associated fibroblast, FABP5, Lipid phosphate phosphatases, Lipid signalling, Liver cancer, LPA, Lysophosphatidic acid, Pancreatic cancer, PDAC, Tumour microenvironment
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/1a2c90d4-d2e5-4afc-b658-7a72822d4328/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2023-03-30
date modified: 2026-07-22T22:23:59Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.104715