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

Autor:	Auciello FR; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Bulusu V; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Oon C; Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon., Tait-Mulder J; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Berry M; Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon., Bhattacharyya S; Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon., Tumanov S; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Allen-Petersen BL; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon., Link J; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon., Kendsersky ND; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon., Vringer E; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Schug M; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Novo D; Cancer Research UK Beatson Institute, Glasgow, UK., Hwang RF; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Evans RM; The Salk Institute for Biological Studies, Gene Expression Laboratory, Howard Hughes Medical Institute, La Jolla, California., Nixon C; Cancer Research UK Beatson Institute, Glasgow, UK., Dorrell C; Oregon Health & Science University Brenden-Colson Center for Pancreatic Care, Portland, Oregon., Morton JP; Cancer Research UK Beatson Institute, Glasgow, UK., Norman JC; Cancer Research UK Beatson Institute, Glasgow, UK., Sears RC; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon., Kamphorst JJ; Cancer Research UK Beatson Institute, Glasgow, UK. shermama@ohsu.edu jurre.kamphorst@glasgow.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Sherman MH; Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon. shermama@ohsu.edu jurre.kamphorst@glasgow.ac.uk.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2019 May; Vol. 9 (5), pp. 617-627. Date of Electronic Publication: 2019 Mar 05.
DOI:	10.1158/2159-8290.CD-18-1212
Abstrakt:	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 . (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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