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Generation of an in vitro 3D PDAC stroma rich spheroid model

Matthew J. Ware, Vazrik Keshishian, Justin J. Law, Jason C. Ho, Carlos A. Favela, Paul Rees Orcid Logo, Billie Smith, Sayeeduddin Mohammad, Rosa F. Hwang, Kimal Rajapakshe, Cristian Coarfa, Shixia Huang, Dean P. Edwards, Stuart J. Corr, Biana Godin, Steven A. Curley

Biomaterials, Volume: 108, Pages: 129 - 142

Swansea University Author: Paul Rees Orcid Logo

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DOI (Published version): 10.1016/j.biomaterials.2016.08.041

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic/stromal reaction, which contributes to the poor clinical outcome of this disease. Therefore, greater understanding of the stroma development and tumor-stroma interactions is highly required. Pancreatic stellate cell...

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Published in: Biomaterials
ISSN: 0142-9612
Published: 2016
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URI: https://cronfa.swan.ac.uk/Record/cronfa29691
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Pancreatic stellate cells (PSC) are myofibroblast-like cells that located in exocrine areas of the pancreas, which as a result of inflammation produced by PDAC migrate and accumulate in the tumor mass, secreting extracellular matrix components and producing the dense PDAC stroma. Currently, only a few orthotopic or ectopic animal tumor models, where PDAC cells are injected into the pancreas or subcutaneous tissue layer, or genetically engineered animals offer tumors that encompass some stromal component. Herein, we report generation of a simple 3D PDAC in vitro micro-tumor model without an addition of external extracellular matrix, which encompasses a rich, dense and active stromal compartment. We have achieved this in vitro model by incorporating PSCs into 3D PDAC cell culture using a modified hanging drop method. It is now known that PSCs are the principal source of fibrosis in the stroma and interact closely with cancer cells to create a tumor facilitatory environment that stimulates local and distant tumor growth. The 3D micro-stroma models are highly reproducible with excellent uniformity, which can be used for PDAC-stroma interaction analysis and high throughput automated drug-screening assays. Additionally, the increased expression of collagenous regions means that molecular based perfusion and cytostaticity of gemcitabine is decreased in our Pancreatic adenocarcinoma stroma spheroids (PDAC-SS) model when compared to spheroids grown without PSCs. We believe this model will allow an improved knowledge of PDAC biology and has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in PDAC and interrupting PSC-PDAC cell interactions so as to inhibit cancer progression.</abstract><type>Journal Article</type><journal>Biomaterials</journal><volume>108</volume><journalNumber/><paginationStart>129</paginationStart><paginationEnd>142</paginationEnd><publisher/><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0142-9612</issnPrint><issnElectronic/><keywords>3D tumor microenvironment; Pancreatic cancer; Stroma; Human pancreatic stellate cells</keywords><publishedDay>1</publishedDay><publishedMonth>11</publishedMonth><publishedYear>2016</publishedYear><publishedDate>2016-11-01</publishedDate><doi>10.1016/j.biomaterials.2016.08.041</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Engineering</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDE</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2021-01-14T13:02:58.3949783</lastEdited><Created>2016-09-02T10:38:08.2636743</Created><path><level id="1">Faculty of Science and Engineering</level><level id="2">School of Engineering and Applied Sciences - Biomedical Engineering</level></path><authors><author><firstname>Matthew J.</firstname><surname>Ware</surname><order>1</order></author><author><firstname>Vazrik</firstname><surname>Keshishian</surname><order>2</order></author><author><firstname>Justin J.</firstname><surname>Law</surname><order>3</order></author><author><firstname>Jason C.</firstname><surname>Ho</surname><order>4</order></author><author><firstname>Carlos A.</firstname><surname>Favela</surname><order>5</order></author><author><firstname>Paul</firstname><surname>Rees</surname><orcid>0000-0002-7715-6914</orcid><order>6</order></author><author><firstname>Billie</firstname><surname>Smith</surname><order>7</order></author><author><firstname>Sayeeduddin</firstname><surname>Mohammad</surname><order>8</order></author><author><firstname>Rosa F.</firstname><surname>Hwang</surname><order>9</order></author><author><firstname>Kimal</firstname><surname>Rajapakshe</surname><order>10</order></author><author><firstname>Cristian</firstname><surname>Coarfa</surname><order>11</order></author><author><firstname>Shixia</firstname><surname>Huang</surname><order>12</order></author><author><firstname>Dean P.</firstname><surname>Edwards</surname><order>13</order></author><author><firstname>Stuart J.</firstname><surname>Corr</surname><order>14</order></author><author><firstname>Biana</firstname><surname>Godin</surname><order>15</order></author><author><firstname>Steven A.</firstname><surname>Curley</surname><order>16</order></author></authors><documents><document><filename>0029691-02092016103912.pdf</filename><originalFilename>ware2016.pdf</originalFilename><uploaded>2016-09-02T10:39:12.9100000</uploaded><type>Output</type><contentLength>4877659</contentLength><contentType>application/pdf</contentType><version>Accepted Manuscript</version><cronfaStatus>true</cronfaStatus><embargoDate>2017-09-02T00:00:00.0000000</embargoDate><documentNotes>Released under the terms of a Creative Commons Attribution Non-Commercial No Derivatives License (CC-BY-NC-ND).</documentNotes><copyrightCorrect>true</copyrightCorrect><language>English</language></document></documents><OutputDurs/></rfc1807>
spelling 2021-01-14T13:02:58.3949783 v2 29691 2016-09-02 Generation of an in vitro 3D PDAC stroma rich spheroid model 537a2fe031a796a3bde99679ee8c24f5 0000-0002-7715-6914 Paul Rees Paul Rees true false 2016-09-02 MEDE Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic/stromal reaction, which contributes to the poor clinical outcome of this disease. Therefore, greater understanding of the stroma development and tumor-stroma interactions is highly required. Pancreatic stellate cells (PSC) are myofibroblast-like cells that located in exocrine areas of the pancreas, which as a result of inflammation produced by PDAC migrate and accumulate in the tumor mass, secreting extracellular matrix components and producing the dense PDAC stroma. Currently, only a few orthotopic or ectopic animal tumor models, where PDAC cells are injected into the pancreas or subcutaneous tissue layer, or genetically engineered animals offer tumors that encompass some stromal component. Herein, we report generation of a simple 3D PDAC in vitro micro-tumor model without an addition of external extracellular matrix, which encompasses a rich, dense and active stromal compartment. We have achieved this in vitro model by incorporating PSCs into 3D PDAC cell culture using a modified hanging drop method. It is now known that PSCs are the principal source of fibrosis in the stroma and interact closely with cancer cells to create a tumor facilitatory environment that stimulates local and distant tumor growth. The 3D micro-stroma models are highly reproducible with excellent uniformity, which can be used for PDAC-stroma interaction analysis and high throughput automated drug-screening assays. Additionally, the increased expression of collagenous regions means that molecular based perfusion and cytostaticity of gemcitabine is decreased in our Pancreatic adenocarcinoma stroma spheroids (PDAC-SS) model when compared to spheroids grown without PSCs. We believe this model will allow an improved knowledge of PDAC biology and has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in PDAC and interrupting PSC-PDAC cell interactions so as to inhibit cancer progression. Journal Article Biomaterials 108 129 142 0142-9612 3D tumor microenvironment; Pancreatic cancer; Stroma; Human pancreatic stellate cells 1 11 2016 2016-11-01 10.1016/j.biomaterials.2016.08.041 COLLEGE NANME Biomedical Engineering COLLEGE CODE MEDE Swansea University 2021-01-14T13:02:58.3949783 2016-09-02T10:38:08.2636743 Faculty of Science and Engineering School of Engineering and Applied Sciences - Biomedical Engineering Matthew J. Ware 1 Vazrik Keshishian 2 Justin J. Law 3 Jason C. Ho 4 Carlos A. Favela 5 Paul Rees 0000-0002-7715-6914 6 Billie Smith 7 Sayeeduddin Mohammad 8 Rosa F. Hwang 9 Kimal Rajapakshe 10 Cristian Coarfa 11 Shixia Huang 12 Dean P. Edwards 13 Stuart J. Corr 14 Biana Godin 15 Steven A. Curley 16 0029691-02092016103912.pdf ware2016.pdf 2016-09-02T10:39:12.9100000 Output 4877659 application/pdf Accepted Manuscript true 2017-09-02T00:00:00.0000000 Released under the terms of a Creative Commons Attribution Non-Commercial No Derivatives License (CC-BY-NC-ND). true English
title Generation of an in vitro 3D PDAC stroma rich spheroid model
spellingShingle Generation of an in vitro 3D PDAC stroma rich spheroid model
Paul Rees
title_short Generation of an in vitro 3D PDAC stroma rich spheroid model
title_full Generation of an in vitro 3D PDAC stroma rich spheroid model
title_fullStr Generation of an in vitro 3D PDAC stroma rich spheroid model
title_full_unstemmed Generation of an in vitro 3D PDAC stroma rich spheroid model
title_sort Generation of an in vitro 3D PDAC stroma rich spheroid model
author_id_str_mv 537a2fe031a796a3bde99679ee8c24f5
author_id_fullname_str_mv 537a2fe031a796a3bde99679ee8c24f5_***_Paul Rees
author Paul Rees
author2 Matthew J. Ware
Vazrik Keshishian
Justin J. Law
Jason C. Ho
Carlos A. Favela
Paul Rees
Billie Smith
Sayeeduddin Mohammad
Rosa F. Hwang
Kimal Rajapakshe
Cristian Coarfa
Shixia Huang
Dean P. Edwards
Stuart J. Corr
Biana Godin
Steven A. Curley
format Journal article
container_title Biomaterials
container_volume 108
container_start_page 129
publishDate 2016
institution Swansea University
issn 0142-9612
doi_str_mv 10.1016/j.biomaterials.2016.08.041
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Biomedical Engineering{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Biomedical Engineering
document_store_str 1
active_str 0
description Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic/stromal reaction, which contributes to the poor clinical outcome of this disease. Therefore, greater understanding of the stroma development and tumor-stroma interactions is highly required. Pancreatic stellate cells (PSC) are myofibroblast-like cells that located in exocrine areas of the pancreas, which as a result of inflammation produced by PDAC migrate and accumulate in the tumor mass, secreting extracellular matrix components and producing the dense PDAC stroma. Currently, only a few orthotopic or ectopic animal tumor models, where PDAC cells are injected into the pancreas or subcutaneous tissue layer, or genetically engineered animals offer tumors that encompass some stromal component. Herein, we report generation of a simple 3D PDAC in vitro micro-tumor model without an addition of external extracellular matrix, which encompasses a rich, dense and active stromal compartment. We have achieved this in vitro model by incorporating PSCs into 3D PDAC cell culture using a modified hanging drop method. It is now known that PSCs are the principal source of fibrosis in the stroma and interact closely with cancer cells to create a tumor facilitatory environment that stimulates local and distant tumor growth. The 3D micro-stroma models are highly reproducible with excellent uniformity, which can be used for PDAC-stroma interaction analysis and high throughput automated drug-screening assays. Additionally, the increased expression of collagenous regions means that molecular based perfusion and cytostaticity of gemcitabine is decreased in our Pancreatic adenocarcinoma stroma spheroids (PDAC-SS) model when compared to spheroids grown without PSCs. We believe this model will allow an improved knowledge of PDAC biology and has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in PDAC and interrupting PSC-PDAC cell interactions so as to inhibit cancer progression.
published_date 2016-11-01T03:36:07Z
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score 11.028886

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