Fine-tuned ECM manipulation via Rho-kinase inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy and metastasis, as assessed by intravital imaging.

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 micro-environmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumour tissue tension and vasculature before chemotherapy can impact tumour response. We used intravital imaging to assess how transient manipulation of the tumour tissue, or ‘priming’, using the pharmaceutical Rho-kinase inhibitor Fasudil affects response to chemotherapy. Intravital FRET imaging of a CDK1 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 sensitised cells to shear stress and impaired colonisation efficiency and fibrotic niche remodelling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumours, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.