Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival
Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic...
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| creator | Pergolini, Ilaria Morales-Oyarvide, Vicente Mino-Kenudson, Mari Honselmann, Kim C Rosenbaum, Matthew W Nahar, Sabikun Kem, Marina Ferrone, Cristina R Lillemoe, Keith D Bardeesy, Nabeel Ryan, David P Thayer, Sarah P Warshaw, Andrew L Fernández-Del Castillo, Carlos Liss, Andrew S |
| description | Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid ( |
| doi_str_mv | 10.1371/journal.pone.0182855 |
| format | Article |
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However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0182855</identifier><identifier>PMID: 28854237</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenocarcinoma ; Adenocarcinoma - pathology ; Adult ; Aged ; Aged, 80 and over ; Animal models ; Animals ; Biodiversity ; Biology ; Biology and Life Sciences ; Carcinoma, Pancreatic Ductal - pathology ; Care and treatment ; Clinical outcomes ; Collagen ; Diagnosis ; Female ; Fibroblasts ; Gene mutation ; Histology ; Hospitals ; Humans ; Immunodeficiency ; Lymph ; Lymph nodes ; Lymph Nodes - pathology ; Lymphatic Metastasis - pathology ; Male ; Medical research ; Medical schools ; Medicine and Health Sciences ; Metastases ; Mice ; Middle Aged ; Neoplasm Transplantation ; Neoplasms, Experimental - pathology ; Pancreas ; Pancreas - pathology ; Pancreatic cancer ; Pancreatic Neoplasms - pathology ; Pathology ; Patients ; Stroma ; Surgery ; Survival ; Survival Analysis ; Transplantation, Heterologous ; Tumors ; Xenografts ; Xenotransplantation</subject><ispartof>PloS one, 2017-08, Vol.12 (8), p.e0182855-e0182855</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Pergolini 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. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Pergolini et al 2017 Pergolini et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-ed2f0f1787a072f51bea671a09f7cd0f630edd35d1745dea02d4627c050aec613</citedby><cites>FETCH-LOGICAL-c692t-ed2f0f1787a072f51bea671a09f7cd0f630edd35d1745dea02d4627c050aec613</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576681/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576681/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28854237$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pergolini, Ilaria</creatorcontrib><creatorcontrib>Morales-Oyarvide, Vicente</creatorcontrib><creatorcontrib>Mino-Kenudson, Mari</creatorcontrib><creatorcontrib>Honselmann, Kim C</creatorcontrib><creatorcontrib>Rosenbaum, Matthew W</creatorcontrib><creatorcontrib>Nahar, Sabikun</creatorcontrib><creatorcontrib>Kem, Marina</creatorcontrib><creatorcontrib>Ferrone, Cristina R</creatorcontrib><creatorcontrib>Lillemoe, Keith D</creatorcontrib><creatorcontrib>Bardeesy, Nabeel</creatorcontrib><creatorcontrib>Ryan, David P</creatorcontrib><creatorcontrib>Thayer, Sarah P</creatorcontrib><creatorcontrib>Warshaw, Andrew L</creatorcontrib><creatorcontrib>Fernández-Del Castillo, Carlos</creatorcontrib><creatorcontrib>Liss, Andrew S</creatorcontrib><title>Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.</description><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - pathology</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biodiversity</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Care and treatment</subject><subject>Clinical outcomes</subject><subject>Collagen</subject><subject>Diagnosis</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Gene mutation</subject><subject>Histology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Immunodeficiency</subject><subject>Lymph</subject><subject>Lymph nodes</subject><subject>Lymph Nodes - pathology</subject><subject>Lymphatic Metastasis - pathology</subject><subject>Male</subject><subject>Medical research</subject><subject>Medical schools</subject><subject>Medicine and Health Sciences</subject><subject>Metastases</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Neoplasm Transplantation</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Pancreas</subject><subject>Pancreas - pathology</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pathology</subject><subject>Patients</subject><subject>Stroma</subject><subject>Surgery</subject><subject>Survival</subject><subject>Survival Analysis</subject><subject>Transplantation, Heterologous</subject><subject>Tumors</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk29rFDEQxhdRbK1-A9EFQfTFncnuJrv3RijFP4VCQatvw1wyuUvJJtdk96wfxu_qXO9aetIXsoEdkt8zM3nCFMVLzqa8bvmHyzimAH66igGnjHdVJ8Sj4pDP6moiK1Y_vhcfFM9yvmRM1J2UT4uDqutEU9XtYfHnYuxjKjEsEtihxzCULpQrGByFE4PJrdGU1xjiDZDLaOk06ISE6NKMegBfgiFAQ9IuxB5Kl0vIOWoHA4l_uWFJxBpTxlJ7F5yOVGAZfVw4TWpLucaEJAqmXEVqJ49p7dbgnxdPLPiML3b_o-LH508XJ18nZ-dfTk-OzyZazqphgqayzPK2a4G1lRV8jiBbDmxmW22YlTVDY2pheNsIg8Aq08iq1UwwQC15fVS83uZd-ZjVztmsyL96Jrqa1lFxuiVMhEu1Sq6H9FtFcOpmI6aFgkSOeFRz2xgh5YwcpojExgLnvJKikXMpZpTr467aOO_RaHI6gd9Lun8S3FIt4loJ0UrZbdp9t0uQ4tWIeVC9yxq9h4BxvOm7qbpatozQN_-gD99uRy2ALuCCjVRXb5KqY8Gqpukk35SdPkDRZ7CnNw1oHe3vCd7vCYgZ8HpYwJizOv3-7f_Z85_77Nt77BLBD8sc_Ti4GPI-2GxBnWLOCe2dyZypzRTduqE2U6R2U0SyV_cf6E50Ozb1X93yG3E</recordid><startdate>20170830</startdate><enddate>20170830</enddate><creator>Pergolini, Ilaria</creator><creator>Morales-Oyarvide, Vicente</creator><creator>Mino-Kenudson, Mari</creator><creator>Honselmann, Kim C</creator><creator>Rosenbaum, Matthew W</creator><creator>Nahar, Sabikun</creator><creator>Kem, Marina</creator><creator>Ferrone, Cristina R</creator><creator>Lillemoe, Keith D</creator><creator>Bardeesy, Nabeel</creator><creator>Ryan, David P</creator><creator>Thayer, Sarah P</creator><creator>Warshaw, Andrew L</creator><creator>Fernández-Del Castillo, Carlos</creator><creator>Liss, Andrew S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20170830</creationdate><title>Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival</title><author>Pergolini, Ilaria ; Morales-Oyarvide, Vicente ; Mino-Kenudson, Mari ; Honselmann, Kim C ; Rosenbaum, Matthew W ; Nahar, Sabikun ; Kem, Marina ; Ferrone, Cristina R ; Lillemoe, Keith D ; Bardeesy, Nabeel ; Ryan, David P ; Thayer, Sarah P ; Warshaw, Andrew L ; Fernández-Del Castillo, Carlos ; Liss, Andrew S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-ed2f0f1787a072f51bea671a09f7cd0f630edd35d1745dea02d4627c050aec613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adenocarcinoma</topic><topic>Adenocarcinoma - 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Academic</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>Pergolini, Ilaria</au><au>Morales-Oyarvide, Vicente</au><au>Mino-Kenudson, Mari</au><au>Honselmann, Kim C</au><au>Rosenbaum, Matthew W</au><au>Nahar, Sabikun</au><au>Kem, Marina</au><au>Ferrone, Cristina R</au><au>Lillemoe, Keith D</au><au>Bardeesy, Nabeel</au><au>Ryan, David P</au><au>Thayer, Sarah P</au><au>Warshaw, Andrew L</au><au>Fernández-Del Castillo, Carlos</au><au>Liss, Andrew S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-08-30</date><risdate>2017</risdate><volume>12</volume><issue>8</issue><spage>e0182855</spage><epage>e0182855</epage><pages>e0182855-e0182855</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28854237</pmid><doi>10.1371/journal.pone.0182855</doi><tpages>e0182855</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-08, Vol.12 (8), p.e0182855-e0182855 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1933958358 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenocarcinoma Adenocarcinoma - pathology Adult Aged Aged, 80 and over Animal models Animals Biodiversity Biology Biology and Life Sciences Carcinoma, Pancreatic Ductal - pathology Care and treatment Clinical outcomes Collagen Diagnosis Female Fibroblasts Gene mutation Histology Hospitals Humans Immunodeficiency Lymph Lymph nodes Lymph Nodes - pathology Lymphatic Metastasis - pathology Male Medical research Medical schools Medicine and Health Sciences Metastases Mice Middle Aged Neoplasm Transplantation Neoplasms, Experimental - pathology Pancreas Pancreas - pathology Pancreatic cancer Pancreatic Neoplasms - pathology Pathology Patients Stroma Surgery Survival Survival Analysis Transplantation, Heterologous Tumors Xenografts Xenotransplantation |
| title | Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T20%3A07%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Tumor%20engraftment%20in%20patient-derived%20xenografts%20of%20pancreatic%20ductal%20adenocarcinoma%20is%20associated%20with%20adverse%20clinicopathological%20features%20and%20poor%20survival&rft.jtitle=PloS%20one&rft.au=Pergolini,%20Ilaria&rft.date=2017-08-30&rft.volume=12&rft.issue=8&rft.spage=e0182855&rft.epage=e0182855&rft.pages=e0182855-e0182855&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0182855&rft_dat=%3Cgale_plos_%3EA502448611%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1933958358&rft_id=info:pmid/28854237&rft_galeid=A502448611&rft_doaj_id=oai_doaj_org_article_bf4d5669542f4d358dfa11126546b659&rfr_iscdi=true |