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A Stromal Lysolipid–Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression
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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. See related commentary by Biffi and Tuveson, p. 578. This article is highlighted in the In This Issue feature, p. 565
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“Autophagy in stromal fibroblasts can generate alanine, which is subsequently used by pancreatic ductal adenocarcinoma (PDAC) cells to fuel the tricarboxylic acid (TCA) cycle126,130,131.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [131]
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“Differential expression of solute carrier proteins (SLCs) can also function to promote a one-way fibroblast-SLC1A4 / PDAC-SLC38A2 exchange axis, enabling the exchange of alanine253.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [253]
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Metadata
- 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., & Sherman, M. H.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Oregon Health & Science University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Kamphorst, Jurre J.
- Sherman, Mara H.
- ORCID
- Auciello, Francesca R.
- Bulusu, Vinay
- Oon, Chet
- Tait-Mulder, Jacqueline
- Bhattacharyya, Sohinee
- Tumanov, Sergey
- Allen-Petersen, Brittany L.
- Link, Jason
- Kendsersky, Nicholas D.
- Vringer, Esmee
- 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.
- Venue
- Cancer Discovery
- Published
- 2019-05-01
- Volume
- 9
- Issue
- 5
- Pages
- 617-627
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6497553
- OpenAlex
- W2920517824
- Cited by
- 332
- References
- 32
- Citations by year
- 2026: 35 · 2025: 34 · 2024: 61 · 2023: 56 · 2022: 50 · 2021: 38 · 2020: 49 · 2019: 9
- FWCI
- 12.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Funders
- Cancer Research UK (C596/A18076, C596/A17196, C50242/A17728)
- National Cancer Institute (CA188259-01, R01CA229580)
- V Foundation (V2017-009)
- American Cancer Society (132898-RSG-18-142-01-CSM)
- Hirshberg Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, pancreatic stellate cells, autotaxin, lysophosphatidic acid, lysophosphatidylcholine, tumor stroma, cancer-associated fibroblasts, lipid metabolism, phosphatidylcholine synthesis, Akt activation, cell proliferation and migration
- MeSH terms
- Lysophospholipase D, Animals, Cell Movement, Disease Models, Animal, Female, Humans, Lysophosphatidylcholines, Male, Mice, Inbred C57BL, Mice, Nude, Pancreatic Neoplasms, Phosphoric Diester Hydrolases, Tumor Cells, Cultured, Signal Transduction, Stromal Cells, Disease Progression, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Proliferation, Pancreatic Stellate Cells
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