Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Sci Transl Med. 2017 Apr 5;9(384):eaai8504. doi: 10.1126/scitranslmed.aai8504.

Abstract

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism
  • Albumin-Bound Paclitaxel / pharmacology
  • Albumin-Bound Paclitaxel / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biosensing Techniques
  • CDC2 Protein Kinase / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Collagen / metabolism
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Disease Progression*
  • Extracellular Matrix / metabolism
  • Humans
  • Liver / pathology
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use*
  • Signal Transduction / drug effects
  • Treatment Outcome
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism
  • src-Family Kinases / metabolism

Substances

  • Albumin-Bound Paclitaxel
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Deoxycytidine
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Collagen
  • gemcitabine
  • src-Family Kinases
  • rho-Associated Kinases
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • fasudil