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

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.

SUBMITTER: Vennin C

PROVIDER: S-EPMC5777504 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Vennin Claire C Chin Venessa T VT Warren Sean C SC Lucas Morghan C MC Herrmann David D Magenau Astrid A Melenec Pauline P Walters Stacey N SN Del Monte-Nieto Gonzalo G Conway James R W JR Nobis Max M Allam Amr H AH McCloy Rachael A RA Currey Nicola N Pinese Mark M Boulghourjian Alice A Zaratzian Anaiis A Adam Arne A S AA Heu Celine C Nagrial Adnan M AM Chou Angela A Steinmann Angela A Drury Alison A Froio Danielle D Giry-Laterriere Marc M Harris Nathanial L E NL Phan Tri T Jain Rohit R Weninger Wolfgang W McGhee Ewan J EJ Whan Renee R Johns Amber L AL Samra Jaswinder S JS Chantrill Lorraine L Gill Anthony J AJ Kohonen-Corish Maija M Harvey Richard P RP Harvey Richard P RP Biankin Andrew V AV Evans T R Jeffry TR Anderson Kurt I KI Grey Shane T ST Ormandy Christopher J CJ Gallego-Ortega David D Wang Yingxiao Y Samuel Michael S MS Sansom Owen J OJ Burgess Andrew A Cox Thomas R TR Morton Jennifer P JP Pajic Marina M Timpson Paul P

Science translational medicine 20170401 384

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. W ...[more]

PMID: 28381539

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Project description:BackgroundThe majority of stress-sensitive genes responds to cold and high light in the same direction, if plants face the stresses for the first time. As shown recently for a small selection of genes of the core environmental stress response cluster, pre-treatment of Arabidopsis thaliana with a 24 h long 4 °C cold stimulus modifies cold regulation of gene expression for up to a week at 20 °C, although the primary cold effects are reverted within the first 24 h. Such memory-based regulation is called priming. Here, we analyse the effect of 24 h cold priming on cold regulation of gene expression on a transcriptome-wide scale and investigate if and how cold priming affects light regulation of gene expression.ResultsCold-priming affected cold and excess light regulation of a small subset of genes. In contrast to the strong gene co-regulation observed upon cold and light stress in non-primed plants, most priming-sensitive genes were regulated in a stressor-specific manner in cold-primed plant. Furthermore, almost as much genes were inversely regulated as co-regulated by a 24 h long 4 °C cold treatment and exposure to heat-filtered high light (800 μmol quanta m- 2 s- 1). Gene ontology enrichment analysis revealed that cold priming preferentially supports expression of genes involved in the defence against plant pathogens upon cold triggering. The regulation took place on the cost of the expression of genes involved in growth regulation and transport. On the contrary, cold priming resulted in stronger expression of genes regulating metabolism and development and weaker expression of defence genes in response to high light triggering. qPCR with independently cultivated and treated replicates confirmed the trends observed in the RNASeq guide experiment.ConclusionA 24 h long priming cold stimulus activates a several days lasting stress memory that controls cold and light regulation of gene expression and adjusts growth and defence regulation in a stressor-specific manner.

Dataset Information

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

Publications

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

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