A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression

Auciello, F. R. et al. (2019) A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discovery, 9(5), pp. 617-627. (doi: 10.1158/2159-8290.CD-18-1212) (PMID:30837243) (PMCID:PMC6497553)

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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.

Item Type:Articles
Additional Information:This work is supported by a Cancer Research UK Career Development Fellowship (C50242/A17728, to J.J. Kamphorst) and by a National Cancer Institute Pathway to Independence Award (CA188259-01) and grant R01CA229580, V Foundation V Scholar Award (V2017-009), American Cancer Society Research Scholar Grant (132898-RSG-18-142-01-CSM), and Hirshberg Foundation Seed Grant (all to M.H. Sherman).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nixon, Mr Colin and Bulusu, Dr Vinay and Tait-Mulder, Dr Jacqueline and Tumanov, Dr Sergey and Morton, Professor Jen and Vringer, Esmee and Norman, Professor James and Novo, David and Kamphorst, Dr Jurre
Authors: Auciello, F. R., Bulusu, V., Oon, C., Tait-Mulder, J., Berry, M., Bhattacharyya, S., Tumanov, S., Allen-Petersen, B. L., Link, J., Kendsersky, N. D., Vringer, E., Schug, M., Novo, D., Hwang, R. F., Evans, R. M., Nixon, C., Dorrell, C., Morton, J. P., Norman, J. C., Sears, R. C., Kamphorst, J. J., and Sherman, M. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Discovery
Publisher:American Association for Cancer Research
ISSN:2159-8274
ISSN (Online):2159-8290
Published Online:05 March 2019
Copyright Holders:Copyright © 2019 American Association for Cancer Research
First Published:First published in Cancer Discovery 9(5):617-627
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170391The effect of tumour microenvironment on the metabolism of pancreatic cancer cellsJurre KamphorstCancer Research UK (CRUK)C50242/A17728CS - Beatson Institute for Cancer Research