The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma
Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we...
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| Veröffentlicht in: | PloS one 2017-07, Vol.12 (7), p.e0180181 |
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| creator | Begum, Asma Ewachiw, Theodore Jung, Clinton Huang, Ally Norberg, K Jessica Marchionni, Luigi McMillan, Ross Penchev, Vesselin Rajeshkumar, N V Maitra, Anirban Wood, Laura Wang, Chenguang Wolfgang, Christopher DeJesus-Acosta, Ana Laheru, Daniel Shapiro, Irina M Padval, Mahesh Pachter, Jonathan A Weaver, David T Rasheed, Zeshaan A Matsui, William |
| description | Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination. |
| doi_str_mv | 10.1371/journal.pone.0180181 |
| format | Article |
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A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0180181</identifier><identifier>PMID: 28692661</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenocarcinoma ; Adhesion ; Aldehyde Dehydrogenase - metabolism ; Animals ; Biology and Life Sciences ; Cancer ; Cancer metastasis ; Carcinoma, Pancreatic Ductal - enzymology ; Carcinoma, Pancreatic Ductal - pathology ; Care and treatment ; Cell cycle ; Cell Line, Tumor ; Cell Movement - drug effects ; Cell Proliferation - drug effects ; Cell Self Renewal - drug effects ; Cell self-renewal ; Chemotherapy ; Clone Cells ; Collagen ; Collagen (type I) ; Collagen Type I - metabolism ; Departments ; Diagnosis ; Drug resistance ; Extracellular matrix ; Extracellular Matrix - drug effects ; Extracellular Matrix - metabolism ; Focal adhesion kinase ; Focal Adhesion Protein-Tyrosine Kinases - metabolism ; Gemcitabine ; Humans ; In vitro methods and tests ; In vivo methods and tests ; Inhibitors ; Integrin beta1 - metabolism ; Integrins ; Kinases ; Medical research ; Medicine ; Medicine and Health Sciences ; Metastases ; Metastasis ; Mice, Nude ; Neoplasm Metastasis ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Oncology ; Paclitaxel ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms ; Pancreatic Neoplasms - enzymology ; Pancreatic Neoplasms - pathology ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Signal Transduction - drug effects ; Stem cell transplantation ; Stem cells ; Tumors ; Well construction ; Xenografts</subject><ispartof>PloS one, 2017-07, Vol.12 (7), p.e0180181</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Begum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.</description><subject>Adenocarcinoma</subject><subject>Adhesion</subject><subject>Aldehyde Dehydrogenase - metabolism</subject><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Cancer</subject><subject>Cancer metastasis</subject><subject>Carcinoma, Pancreatic Ductal - enzymology</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Care and treatment</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Self Renewal - drug effects</subject><subject>Cell self-renewal</subject><subject>Chemotherapy</subject><subject>Clone Cells</subject><subject>Collagen</subject><subject>Collagen (type I)</subject><subject>Collagen Type I - 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Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Begum, Asma</au><au>Ewachiw, Theodore</au><au>Jung, Clinton</au><au>Huang, Ally</au><au>Norberg, K Jessica</au><au>Marchionni, Luigi</au><au>McMillan, Ross</au><au>Penchev, Vesselin</au><au>Rajeshkumar, N V</au><au>Maitra, Anirban</au><au>Wood, Laura</au><au>Wang, Chenguang</au><au>Wolfgang, Christopher</au><au>DeJesus-Acosta, Ana</au><au>Laheru, Daniel</au><au>Shapiro, Irina M</au><au>Padval, Mahesh</au><au>Pachter, Jonathan A</au><au>Weaver, David T</au><au>Rasheed, Zeshaan A</au><au>Matsui, William</au><au>Batra, Surinder K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-07-10</date><risdate>2017</risdate><volume>12</volume><issue>7</issue><spage>e0180181</spage><pages>e0180181-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28692661</pmid><doi>10.1371/journal.pone.0180181</doi><tpages>e0180181</tpages><orcidid>https://orcid.org/0000-0002-3088-0964</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-07, Vol.12 (7), p.e0180181 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1917697069 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenocarcinoma Adhesion Aldehyde Dehydrogenase - metabolism Animals Biology and Life Sciences Cancer Cancer metastasis Carcinoma, Pancreatic Ductal - enzymology Carcinoma, Pancreatic Ductal - pathology Care and treatment Cell cycle Cell Line, Tumor Cell Movement - drug effects Cell Proliferation - drug effects Cell Self Renewal - drug effects Cell self-renewal Chemotherapy Clone Cells Collagen Collagen (type I) Collagen Type I - metabolism Departments Diagnosis Drug resistance Extracellular matrix Extracellular Matrix - drug effects Extracellular Matrix - metabolism Focal adhesion kinase Focal Adhesion Protein-Tyrosine Kinases - metabolism Gemcitabine Humans In vitro methods and tests In vivo methods and tests Inhibitors Integrin beta1 - metabolism Integrins Kinases Medical research Medicine Medicine and Health Sciences Metastases Metastasis Mice, Nude Neoplasm Metastasis Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Oncology Paclitaxel Pancreas Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - enzymology Pancreatic Neoplasms - pathology Protein Kinase Inhibitors - pharmacology Proteins Signal Transduction - drug effects Stem cell transplantation Stem cells Tumors Well construction Xenografts |
| title | The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma |
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