期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 9, 期 384, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aai8504
关键词
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资金
- National Health and Medical Research Council (NHMRC)
- Cancer Council NSW
- Cancer Australia
- Tour de Cure grants
- Cancer Institute NSW
- Australian Research Council Future Fellowships
- Avner Pancreatic Cancer Foundation
- Lens Ainsworth and Philip Hemstritch Pancreatic Cancer Fellowships
- Sydney Catalyst scholarships
- Royal Australasian College of Physicians Research Foundation scholarships
- Pancare Australia stipend
- NHMRC scholarships
- Cancer Research UK core grant
- Patricia Helen Guest Fellowship
- Celgene
- Bristol-Myers Squibb
- AstraZeneca
- Bayer
- Roche
- Basilea
- MRC [MR/N005813/1] Funding Source: UKRI
- Cancer Research UK [22311, 11650, 12946, 23526, 22533, 15565] Funding Source: researchfish
- Medical Research Council [MR/N005813/1] Funding Source: researchfish
- Pancreatic Cancer UK [FLF2015_04_Glasgow] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20409] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [21139] Funding Source: researchfish
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 Forster 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.
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