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 Stahelin, Margaret Schwarz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)458-466
Number of pages9
JournalBiochemical Pharmacology
Volume156
DOIs
StatePublished - Oct 1 2018

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Neoplastic Stem Cells
Stem cells
Pancreatic Neoplasms
Cell Movement
Adenocarcinoma
Tumors
Neoplasms
Sphingolipids
Cytotoxins
ceramide 1-phosphate
Extracellular Vesicles
Animals
Chemical activation
Cells
Neoplasm Metastasis
Mortality
Enzymes
Growth

Keywords

  • Ceramide-1-phosphate
  • Ceramides
  • Sphingolipids
  • Tumor dissemination

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Pancreatic ductal adenocarcinoma cell secreted extracellular vesicles containing ceramide-1-phosphate promote pancreatic cancer stem cell motility. / Kuc, Norbert; Doermann, Allison; Shirey, Carolyn; Lee, Daniel D.; Lowe, Chinn Woan; Awasthi, Niranjan; Schwarz, Roderich E.; Stahelin, Robert; Schwarz, Margaret.

In: Biochemical Pharmacology, Vol. 156, 01.10.2018, p. 458-466.

Research output: Contribution to journalArticle

Kuc, Norbert ; Doermann, Allison ; Shirey, Carolyn ; Lee, Daniel D. ; Lowe, Chinn Woan ; Awasthi, Niranjan ; Schwarz, Roderich E. ; Stahelin, Robert ; Schwarz, Margaret. / Pancreatic ductal adenocarcinoma cell secreted extracellular vesicles containing ceramide-1-phosphate promote pancreatic cancer stem cell motility. In: Biochemical Pharmacology. 2018 ; Vol. 156. pp. 458-466.
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