Direct Interactions with Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function

Asma Begum, Ross H. McMillan, Yu Tai Chang, Vesselin R. Penchev, N. V. Rajeshkumar, Anirban Maitra, Michael G. Goggins, James R. Eshelman, Christopher L. Wolfgang, Zeshaan A. Rasheed, William Matsui

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Objective Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs). Methods Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin-focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor. Results Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth. Conclusion Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.

Original languageEnglish (US)
Pages (from-to)329-334
Number of pages6
JournalPancreas
Volume48
Issue number3
DOIs
StatePublished - Mar 1 2019

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Neoplastic Stem Cells
Pancreatic Neoplasms
Adenocarcinoma
Focal Adhesion Protein-Tyrosine Kinases
Integrins
Focal Adhesion Kinase 1
Growth
Fibroblasts
Cancer-Associated Fibroblasts
Collagen Type I
Tumor Cell Line
Drug Resistance
Small Interfering RNA
Cell Movement
Flow Cytometry
Phosphotransferases
Collagen

Keywords

  • cancer stem cell
  • cancer-associated fibroblast
  • pancreatic cancer
  • reactive stroma
  • tumor microenvironment

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

Cite this

Direct Interactions with Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function. / Begum, Asma; McMillan, Ross H.; Chang, Yu Tai; Penchev, Vesselin R.; Rajeshkumar, N. V.; Maitra, Anirban; Goggins, Michael G.; Eshelman, James R.; Wolfgang, Christopher L.; Rasheed, Zeshaan A.; Matsui, William.

In: Pancreas, Vol. 48, No. 3, 01.03.2019, p. 329-334.

Research output: Contribution to journalArticle

Begum, A, McMillan, RH, Chang, YT, Penchev, VR, Rajeshkumar, NV, Maitra, A, Goggins, MG, Eshelman, JR, Wolfgang, CL, Rasheed, ZA & Matsui, W 2019, 'Direct Interactions with Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function', Pancreas, vol. 48, no. 3, pp. 329-334. https://doi.org/10.1097/MPA.0000000000001249
Begum, Asma ; McMillan, Ross H. ; Chang, Yu Tai ; Penchev, Vesselin R. ; Rajeshkumar, N. V. ; Maitra, Anirban ; Goggins, Michael G. ; Eshelman, James R. ; Wolfgang, Christopher L. ; Rasheed, Zeshaan A. ; Matsui, William. / Direct Interactions with Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function. In: Pancreas. 2019 ; Vol. 48, No. 3. pp. 329-334.
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abstract = "Objective Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs). Methods Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin-focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor. Results Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth. Conclusion Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.",
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AU - Begum, Asma

AU - McMillan, Ross H.

AU - Chang, Yu Tai

AU - Penchev, Vesselin R.

AU - Rajeshkumar, N. V.

AU - Maitra, Anirban

AU - Goggins, Michael G.

AU - Eshelman, James R.

AU - Wolfgang, Christopher L.

AU - Rasheed, Zeshaan A.

AU - Matsui, William

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N2 - Objective Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs). Methods Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin-focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor. Results Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth. Conclusion Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.

AB - Objective Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs). Methods Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin-focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor. Results Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth. Conclusion Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.

KW - cancer stem cell

KW - cancer-associated fibroblast

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KW - reactive stroma

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