Development of a multicellular pancreatic tumor microenvironment system using patient-derived tumor cells

The development of drugs to treat cancer is hampered by the inefficiency of translating pre-clinical in vitro monoculture and mouse studies into clinical benefit. There is a critical need to improve the accuracy of evaluating pre-clinical drug efficacy through the development of more physiologically...

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Veröffentlicht in:Lab on a chip Jg. 19; H. 7; S. 1193
Hauptverfasser: Gioeli, Daniel, Snow, Chelsi J, Simmers, Michael B, Hoang, Stephen A, Figler, Robert A, Allende, J Ashe, Roller, Devin G, Parsons, J Thomas, Wulfkuhle, Julia D, Petricoin, Emanuel F, Bauer, Todd W, Wamhoff, Brian R
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England 27.03.2019
Schlagworte:
Biomimetics - methods
Carcinoma, Pancreatic Ductal - pathology
Cell Proliferation - drug effects
Humans
Tumor Microenvironment - drug effects
ISSN:1473-0189, 1473-0189
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Abstract The development of drugs to treat cancer is hampered by the inefficiency of translating pre-clinical in vitro monoculture and mouse studies into clinical benefit. There is a critical need to improve the accuracy of evaluating pre-clinical drug efficacy through the development of more physiologically relevant models. In this study, a human triculture 3D in vitro tumor microenvironment system (TMES) was engineered to accurately mimic the tumor microenvironment. The TMES recapitulates tumor hemodynamics and biological transport with co-cultured human microvascular endothelial cells, pancreatic ductal adenocarcinoma, and pancreatic stellate cells. We demonstrate that significant tumor cell transcriptomic changes occur in the TMES that correlate with the in vivo xenograft and patient transcriptome. Treatment with therapeutically relevant doses of chemotherapeutics yields responses paralleling the patients' clinical responses. Thus, this model provides a unique platform to rigorously evaluate novel therapies and is amenable to using patient tumor material directly, with applicability for patient avatars.
AbstractList The development of drugs to treat cancer is hampered by the inefficiency of translating pre-clinical in vitro monoculture and mouse studies into clinical benefit. There is a critical need to improve the accuracy of evaluating pre-clinical drug efficacy through the development of more physiologically relevant models. In this study, a human triculture 3D in vitro tumor microenvironment system (TMES) was engineered to accurately mimic the tumor microenvironment. The TMES recapitulates tumor hemodynamics and biological transport with co-cultured human microvascular endothelial cells, pancreatic ductal adenocarcinoma, and pancreatic stellate cells. We demonstrate that significant tumor cell transcriptomic changes occur in the TMES that correlate with the in vivo xenograft and patient transcriptome. Treatment with therapeutically relevant doses of chemotherapeutics yields responses paralleling the patients' clinical responses. Thus, this model provides a unique platform to rigorously evaluate novel therapies and is amenable to using patient tumor material directly, with applicability for patient avatars.The development of drugs to treat cancer is hampered by the inefficiency of translating pre-clinical in vitro monoculture and mouse studies into clinical benefit. There is a critical need to improve the accuracy of evaluating pre-clinical drug efficacy through the development of more physiologically relevant models. In this study, a human triculture 3D in vitro tumor microenvironment system (TMES) was engineered to accurately mimic the tumor microenvironment. The TMES recapitulates tumor hemodynamics and biological transport with co-cultured human microvascular endothelial cells, pancreatic ductal adenocarcinoma, and pancreatic stellate cells. We demonstrate that significant tumor cell transcriptomic changes occur in the TMES that correlate with the in vivo xenograft and patient transcriptome. Treatment with therapeutically relevant doses of chemotherapeutics yields responses paralleling the patients' clinical responses. Thus, this model provides a unique platform to rigorously evaluate novel therapies and is amenable to using patient tumor material directly, with applicability for patient avatars.
The development of drugs to treat cancer is hampered by the inefficiency of translating pre-clinical in vitro monoculture and mouse studies into clinical benefit. There is a critical need to improve the accuracy of evaluating pre-clinical drug efficacy through the development of more physiologically relevant models. In this study, a human triculture 3D in vitro tumor microenvironment system (TMES) was engineered to accurately mimic the tumor microenvironment. The TMES recapitulates tumor hemodynamics and biological transport with co-cultured human microvascular endothelial cells, pancreatic ductal adenocarcinoma, and pancreatic stellate cells. We demonstrate that significant tumor cell transcriptomic changes occur in the TMES that correlate with the in vivo xenograft and patient transcriptome. Treatment with therapeutically relevant doses of chemotherapeutics yields responses paralleling the patients' clinical responses. Thus, this model provides a unique platform to rigorously evaluate novel therapies and is amenable to using patient tumor material directly, with applicability for patient avatars.
Author Roller, Devin G
Parsons, J Thomas
Snow, Chelsi J
Wamhoff, Brian R
Hoang, Stephen A
Petricoin, Emanuel F
Bauer, Todd W
Gioeli, Daniel
Allende, J Ashe
Wulfkuhle, Julia D
Simmers, Michael B
Figler, Robert A
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  givenname: Daniel
  surname: Gioeli
  fullname: Gioeli, Daniel
  email: dgg3f@virginia.edu
  organization: Departments of Microbiology, Immunology, and Cancer Biology, Virginia, USA. dgg3f@virginia.edu
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  givenname: Chelsi J
  surname: Snow
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  givenname: Michael B
  surname: Simmers
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  givenname: Stephen A
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  surname: Figler
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  givenname: J Ashe
  surname: Allende
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  givenname: Devin G
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  surname: Bauer
  fullname: Bauer, Todd W
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  givenname: Brian R
  surname: Wamhoff
  fullname: Wamhoff, Brian R
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30839006$$D View this record in MEDLINE/PubMed
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SubjectTerms Biomimetics - methods
Carcinoma, Pancreatic Ductal - pathology
Cell Proliferation - drug effects
Humans
Tumor Microenvironment - drug effects
Title Development of a multicellular pancreatic tumor microenvironment system using patient-derived tumor cells
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