A Stromal Lysolipid-Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression

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...

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Veröffentlicht in:Cancer discovery Jg. 9; H. 5; S. 617
Hauptverfasser: Auciello, Francesca R, Bulusu, Vinay, Oon, Chet, Tait-Mulder, Jacqueline, Berry, Mark, Bhattacharyya, Sohinee, Tumanov, Sergey, Allen-Petersen, Brittany L, Link, Jason, Kendsersky, Nicholas D, Vringer, Esmee, Schug, Michelle, Novo, David, Hwang, Rosa F, Evans, Ronald M, Nixon, Colin, Dorrell, Craig, Morton, Jennifer P, Norman, Jim C, Sears, Rosalie C, Kamphorst, Jurre J, Sherman, Mara H
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.05.2019
Schlagworte:
Animals
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Cell Movement
Cell Proliferation
Disease Models, Animal
Disease Progression
Female
Humans
Lysophosphatidylcholines - metabolism
Male
Mice, Inbred C57BL
Mice, Nude
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Pancreatic Stellate Cells - metabolism
Pancreatic Stellate Cells - pathology
Phosphoric Diester Hydrolases - metabolism
Signal Transduction
Stromal Cells - metabolism
Stromal Cells - pathology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
ISSN:2159-8290, 2159-8290
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Zusammenfassung: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 . 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. . .
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:2159-8290
2159-8290
DOI:10.1158/2159-8290.CD-18-1212