A Stromal Lysolipid-Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression.
Animals
Carcinoma, Pancreatic Ductal
/ metabolism
Cell Movement
Cell Proliferation
Disease Models, Animal
Disease Progression
Female
Humans
Lysophosphatidylcholines
/ metabolism
Male
Mice, Inbred C57BL
Mice, Nude
Pancreatic Neoplasms
/ metabolism
Pancreatic Stellate Cells
/ metabolism
Phosphoric Diester Hydrolases
/ metabolism
Signal Transduction
Stromal Cells
/ metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
12
10
2018
revised:
03
02
2019
accepted:
28
02
2019
pubmed:
7
3
2019
medline:
2
6
2020
entrez:
7
3
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 30837243
pii: 2159-8290.CD-18-1212
doi: 10.1158/2159-8290.CD-18-1212
pmc: PMC6497553
mid: NIHMS1523395
doi:
Substances chimiques
Lysophosphatidylcholines
0
Phosphoric Diester Hydrolases
EC 3.1.4.-
alkylglycerophosphoethanolamine phosphodiesterase
EC 3.1.4.39
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
617-627Subventions
Organisme : Cancer Research UK
ID : C50242/A17728
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R00 CA188259
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA188259
Pays : United States
Organisme : Cancer Research UK
ID : C596/A18076
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA186241
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196228
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA229580
Pays : United States
Organisme : Cancer Research UK
ID : C596/A17196
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P01058X/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2019 American Association for Cancer Research.
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