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 |
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| 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: | Norman, Professor James and Kamphorst, Dr Jurre and Fontinha da Silva Novo, David and Nixon, Mr Colin and Bulusu, Dr Vinay and Tait-Mulder, Dr Jacqueline and Tumanov, Dr Sergey and Vringer, Esmee and Morton, Professor Jen |
| 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 > School 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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