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Biochemical pharmacology
10, 2018;156 458-466.

Pancreatic ductal adenocarcinoma cell secreted extracellular vesicles containing ceramide-1-phosphate promote pancreatic cancer stem cell motility.

Norbert Kuc, Allison Doermann, Carolyn Shirey, Daniel D Lee, Chinn-Woan Lowe, Niranjan Awasthi, Roderich E Schwarz, Robert V Stahelin, Margaret A Schwarz
Author Information
  1. Norbert Kuc: Department of Biological Sciences, University of Notre Dame, United States.
  2. Allison Doermann: Department of Biological Sciences, University of Notre Dame, United States.
  3. Carolyn Shirey: Department of Chemistry and Biochemistry, University of Notre Dame, United States.
  4. Daniel D Lee: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, United States; Department of Pediatrics, Indiana University School of Medicine, United States.
  5. Chinn-Woan Lowe: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, United States.
  6. Niranjan Awasthi: Department of Surgery, Indiana University School of Medicine, United States.
  7. Roderich E Schwarz: Department of Surgery, Indiana University School of Medicine, United States; Department of Goshen Center for Cancer Care, Goshen, IN, United States.
  8. Robert V Stahelin: Department of Chemistry and Biochemistry, University of Notre Dame, United States; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, United States.
  9. Margaret A Schwarz: Department of Chemistry and Biochemistry, University of Notre Dame, United States; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, United States; Department of Pediatrics, Indiana University School of Medicine, United States. Electronic address: schwarma@iu.edu.
PMID: 30222969 DOI: 10.1016/j.bcp.2018.09.017

Abstract

The high mortality rate associated with pancreatic ductal adenocarcinoma (PDAC) is in part due to lack of effective therapy for this highly chemoresistant tumor. Cancer stem cells, a subset of cancer cells responsible for tumor initiation and metastasis, are not targeted by conventional cytotoxic agents, which renders the identification of factors that facilitate cancer stem cell activation useful in defining targetable mechanisms. We determined that bioactive sphingolipid induced migration of pancreatic cancer stem cells (PCSC) and signaling was specific to ceramide-1-phosphate (C1P). Furthermore, PDAC cells were identified as a rich source of C1P. Importantly, PDAC cells express the C1P converting enzyme ceramide kinase (CerK), secrete C1P-containing extracellular vesicles that mediate PCSC migration, and when co-injected with PCSC reduce animal survival in a PDAC peritoneal dissemination model. Our findings suggest that PDAC secrete C1P-containing extracellular vesicles as a means of recruiting PCSC to sustain tumor growth therefore making C1P release a mechanism that could facilitate tumor progression.

Keywords

Ceramide-1-phosphate Ceramides Sphingolipids Tumor dissemination

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Grants

  1. R01 HL114977/NHLBI NIH HHS

MeSH Term

Adenocarcinoma
Animals
Carcinoma, Pancreatic Ductal
Cell Adhesion
Cell Line, Tumor
Cell Movement
Ceramides
Extracellular Vesicles
Fibronectins
Humans
Mice
Mice, SCID
Neoplasms, Experimental
Neoplastic Stem Cells
Pancreatic Neoplasms
Sphingolipids

Chemicals

Ceramides
Fibronectins
Sphingolipids
ceramide 1-phosphate
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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