Format

Send to

Choose Destination
Cancer Discov. 2019 May;9(5):617-627. doi: 10.1158/2159-8290.CD-18-1212. Epub 2019 Mar 5.

A Stromal Lysolipid-Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression.

Author information

1
Cancer Research UK Beatson Institute, Glasgow, UK.
2
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
3
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon.
4
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon.
5
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
The Salk Institute for Biological Studies, Gene Expression Laboratory, Howard Hughes Medical Institute, La Jolla, California.
7
Oregon Health & Science University Brenden-Colson Center for Pancreatic Care, Portland, Oregon.
8
Cancer Research UK Beatson Institute, Glasgow, UK. shermama@ohsu.edu jurre.kamphorst@glasgow.ac.uk.
9
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon. shermama@ohsu.edu jurre.kamphorst@glasgow.ac.uk.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features transdifferentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin-LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. SIGNIFICANCE: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration.See related commentary by Biffi and Tuveson, p. 578.This article is highlighted in the In This Issue feature, p. 565.

PMID:
30837243
PMCID:
PMC6497553
[Available on 2019-11-01]
DOI:
10.1158/2159-8290.CD-18-1212

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center