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

Vennin, C; Chin, VT; Warren, SC; Lucas, MC; Herrmann, D; Magenau, A; Melenec, P; Walters, SN; Del Monte-Nieto, G; Conway, JRW; Nobis, M; Allam, AH; McCloy, RA; Currey, N; Pinese, M; Boulghourjian, A; Zaratzian, A; Adam, AAS; Heu, C; Nagrial, AM; Chou, A; Steinmann, A; Drury, A; Froio, D; Giry-Laterriere, M; Harris, NLE; Phan, T; Jain, R; Weninger, W; McGhee, EJ; Whan, R; Johns, AL; Samra, JS; Chantrill, L; Gill, AJ; Kohonen-Corish, M; Harvey, RP; Biankin, AV; Australian Pancreatic Cancer Genome Initiative (APGI),; Evans, TRJ; Anderson, KI; Grey, ST; Ormandy, CJ; Gallego-Ortega, D; Wang, Y; Samuel, MS; Sansom, OJ; Burgess, A; Cox, TR; Morton, JP; Pajic, M; Timpson, P

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

Vennin, C Chin, VT Warren, SC Lucas, MC Herrmann, D Magenau, A Melenec, P Walters, SN Del Monte-Nieto, G Conway, JRW Nobis, M Allam, AH McCloy, RA Currey, N Pinese, M Boulghourjian, A Zaratzian, A Adam, AAS Heu, C Nagrial, AM Chou, A Steinmann, A Drury, A Froio, D Giry-Laterriere, M Harris, NLE Phan, T Jain, R Weninger, W McGhee, EJ Whan, R Johns, AL Samra, JS Chantrill, L Gill, AJ Kohonen-Corish, M

Harvey, RP Biankin, AV Australian Pancreatic Cancer Genome Initiative (APGI), Evans, TRJ Anderson, KI Grey, ST Ormandy, CJ Gallego-Ortega, D Wang, Y Samuel, MS Sansom, OJ Burgess, A Cox, TR Morton, JP Pajic, M Timpson, P

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Publisher:: AMER ASSOC ADVANCEMENT SCIENCE
Publication Type:: Journal Article
Citation:: Sci Transl Med, 2017, 9, (384)
Issue Date:: 2017-04-05

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Field	Value	Language
dc.contributor.author	Vennin, C
dc.contributor.author	Chin, VT
dc.contributor.author	Warren, SC
dc.contributor.author	Lucas, MC
dc.contributor.author	Herrmann, D
dc.contributor.author	Magenau, A
dc.contributor.author	Melenec, P
dc.contributor.author	Walters, SN
dc.contributor.author	Del Monte-Nieto, G
dc.contributor.author	Conway, JRW
dc.contributor.author	Nobis, M
dc.contributor.author	Allam, AH
dc.contributor.author	McCloy, RA
dc.contributor.author	Currey, N
dc.contributor.author	Pinese, M
dc.contributor.author	Boulghourjian, A
dc.contributor.author	Zaratzian, A
dc.contributor.author	Adam, AAS
dc.contributor.author	Heu, C
dc.contributor.author	Nagrial, AM
dc.contributor.author	Chou, A
dc.contributor.author	Steinmann, A
dc.contributor.author	Drury, A
dc.contributor.author	Froio, D
dc.contributor.author	Giry-Laterriere, M
dc.contributor.author	Harris, NLE
dc.contributor.author	Phan, T
dc.contributor.author	Jain, R
dc.contributor.author	Weninger, W
dc.contributor.author	McGhee, EJ
dc.contributor.author	Whan, R
dc.contributor.author	Johns, AL
dc.contributor.author	Samra, JS
dc.contributor.author	Chantrill, L
dc.contributor.author	Gill, AJ
dc.contributor.author	Kohonen-Corish, M https://orcid.org/0000-0002-4073-1479
dc.contributor.author	Harvey, RP
dc.contributor.author	Biankin, AV
dc.contributor.author	Australian Pancreatic Cancer Genome Initiative (APGI),
dc.contributor.author	Evans, TRJ
dc.contributor.author	Anderson, KI
dc.contributor.author	Grey, ST
dc.contributor.author	Ormandy, CJ
dc.contributor.author	Gallego-Ortega, D
dc.contributor.author	Wang, Y
dc.contributor.author	Samuel, MS
dc.contributor.author	Sansom, OJ
dc.contributor.author	Burgess, A
dc.contributor.author	Cox, TR
dc.contributor.author	Morton, JP
dc.contributor.author	Pajic, M
dc.contributor.author	Timpson, P
dc.date.accessioned	2022-04-13T12:49:28Z
dc.date.available	2017-03-04
dc.date.available	2022-04-13T12:49:28Z
dc.date.issued	2017-04-05
dc.identifier.citation	Sci Transl Med, 2017, 9, (384)
dc.identifier.issn	1946-6234
dc.identifier.issn	1946-6242
dc.identifier.uri	http://hdl.handle.net/10453/156230
dc.description.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.
dc.format	Print
dc.language	eng
dc.publisher	AMER ASSOC ADVANCEMENT SCIENCE
dc.relation.ispartof	Sci Transl Med
dc.relation.isbasedon	10.1126/scitranslmed.aai8504
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.mesh	1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
dc.subject.mesh	Actin Cytoskeleton
dc.subject.mesh	Albumin-Bound Paclitaxel
dc.subject.mesh	Animals
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Biosensing Techniques
dc.subject.mesh	CDC2 Protein Kinase
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Collagen
dc.subject.mesh	Deoxycytidine
dc.subject.mesh	Disease Progression
dc.subject.mesh	Extracellular Matrix
dc.subject.mesh	Humans
dc.subject.mesh	Liver
dc.subject.mesh	Mice
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Neoplasm Metastasis
dc.subject.mesh	Pancreatic Neoplasms
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	rho-Associated Kinases
dc.subject.mesh	src-Family Kinases
dc.subject.mesh	Liver
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Extracellular Matrix
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Pancreatic Neoplasms
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Neoplasm Metastasis
dc.subject.mesh	Disease Progression
dc.subject.mesh	1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
dc.subject.mesh	Collagen
dc.subject.mesh	CDC2 Protein Kinase
dc.subject.mesh	src-Family Kinases
dc.subject.mesh	Deoxycytidine
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Biosensing Techniques
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	rho-Associated Kinases
dc.subject.mesh	Actin Cytoskeleton
dc.subject.mesh	Albumin-Bound Paclitaxel
dc.title	Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.
dc.type	Journal Article
utslib.citation.volume	9
utslib.location.activity	United States
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.date.updated	2022-04-13T12:49:24Z
pubs.issue	384
pubs.publication-status	Published
pubs.volume	9
utslib.citation.issue	384

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/156230