The Extracellular Matrix and Focal Adhesion Kinase Signaling Regulate Cancer Stem Cell Function in Pancreatic Ductal Adenocarcinoma

PLoS One. 2017 Jul 10;12(7):e0180181. doi: 10.1371/journal.pone.0180181. eCollection 2017.

Abstract

Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.

MeSH terms

  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Carcinoma, Pancreatic Ductal / enzymology*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Self Renewal / drug effects
  • Clone Cells
  • Collagen Type I / metabolism
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Humans
  • Integrin beta1 / metabolism
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / pathology*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction* / drug effects

Substances

  • Collagen Type I
  • Integrin beta1
  • Protein Kinase Inhibitors
  • Aldehyde Dehydrogenase
  • Focal Adhesion Protein-Tyrosine Kinases

Supplementary concepts

  • Pancreatic Carcinoma