Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer
Purpose We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance. Methods PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models....
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| Veröffentlicht in: | Cellular oncology (Dordrecht) 2022-10, Vol.45 (5), p.1019-1036 |
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| creator | Xian, Linfeng Zhao, Pei Chen, Xi Wei, Zhimin Ji, Hongxiang Zhao, Jun Liu, Wenbin Li, Zishuai Liu, Donghong Han, Xue Qian, Youwen Dong, Hui Zhou, Xiong Fan, Junyan Zhu, Xiaoqiong Yin, Jianhua Tan, Xiaojie Jiang, Dongming Yu, Hongping Cao, Guangwen |
| description | Purpose
We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance.
Methods
PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing.
Results
Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days,
p
= 2.28 × 10
−13
). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness– and epithelial–mesenchymal transition (EMT)–related gene sets were found to be upregulated, whereas liver development– and liver specific molecule–related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis.
Conclusions
HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC. |
| doi_str_mv | 10.1007/s13402-022-00707-3 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2707875155</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2726044542</sourcerecordid><originalsourceid>FETCH-LOGICAL-c352t-70270f7fa37400c880bb25dd2a384f2c074a6de438824594ff5a579e6556cf4a3</originalsourceid><addsrcrecordid>eNp90U9LwzAYBvAiCg7dF_AU8OLBapo_TXeUoU4YeNFzyJI3NaNLtqQV9u3N7FDwYCAkh9_zkvAUxVWF7yqMxX2qKMOkxCRvLLAo6UkxIaSqSspoffpzJ815MU1pjfNidVXzelKEBfQQQwseXL-_Rc5_QATfI-UNUno3uAgGmTi0KEJyqVdeQ1Zoq3qXXWkgus9MQmyVD86gTTDQJRQs2ka3UXGPugwi0odkvCzOrOoSTI_nRfH-9Pg2X5TL1-eX-cOy1JSTvhSYCGyFVVQwjHXT4NWKcGOIog2zRGPBVG2A0aYhjM-YtVxxMYOa81pbpuhFcTPO3cawGyD1cuOShq5THsKQZB4vGsErzjO9_kPXYYg-vy4rUmPGOCNZkVHpGFKKYOXxe7LC8lCDHGuQuQb5XYOkOUTHUMrYtxB_R_-T-gID-Yqj</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2726044542</pqid></control><display><type>article</type><title>Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer</title><source>SpringerLink Journals - AutoHoldings</source><creator>Xian, Linfeng ; Zhao, Pei ; Chen, Xi ; Wei, Zhimin ; Ji, Hongxiang ; Zhao, Jun ; Liu, Wenbin ; Li, Zishuai ; Liu, Donghong ; Han, Xue ; Qian, Youwen ; Dong, Hui ; Zhou, Xiong ; Fan, Junyan ; Zhu, Xiaoqiong ; Yin, Jianhua ; Tan, Xiaojie ; Jiang, Dongming ; Yu, Hongping ; Cao, Guangwen</creator><creatorcontrib>Xian, Linfeng ; Zhao, Pei ; Chen, Xi ; Wei, Zhimin ; Ji, Hongxiang ; Zhao, Jun ; Liu, Wenbin ; Li, Zishuai ; Liu, Donghong ; Han, Xue ; Qian, Youwen ; Dong, Hui ; Zhou, Xiong ; Fan, Junyan ; Zhu, Xiaoqiong ; Yin, Jianhua ; Tan, Xiaojie ; Jiang, Dongming ; Yu, Hongping ; Cao, Guangwen</creatorcontrib><description>Purpose
We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance.
Methods
PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing.
Results
Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days,
p
= 2.28 × 10
−13
). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness– and epithelial–mesenchymal transition (EMT)–related gene sets were found to be upregulated, whereas liver development– and liver specific molecule–related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis.
Conclusions
HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC.</description><identifier>ISSN: 2211-3428</identifier><identifier>EISSN: 2211-3436</identifier><identifier>DOI: 10.1007/s13402-022-00707-3</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Drug resistance ; Drug screening ; Gene expression ; Hepatocellular carcinoma ; Kinases ; Liver cancer ; Mesenchyme ; Oncology ; Organoids ; Original Article ; Pathology ; Patients ; Signal transduction ; TOR protein ; Tumors ; Xenografts</subject><ispartof>Cellular oncology (Dordrecht), 2022-10, Vol.45 (5), p.1019-1036</ispartof><rights>Springer Nature Switzerland AG 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c352t-70270f7fa37400c880bb25dd2a384f2c074a6de438824594ff5a579e6556cf4a3</citedby><cites>FETCH-LOGICAL-c352t-70270f7fa37400c880bb25dd2a384f2c074a6de438824594ff5a579e6556cf4a3</cites><orcidid>0000-0002-8094-1278</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s13402-022-00707-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s13402-022-00707-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids></links><search><creatorcontrib>Xian, Linfeng</creatorcontrib><creatorcontrib>Zhao, Pei</creatorcontrib><creatorcontrib>Chen, Xi</creatorcontrib><creatorcontrib>Wei, Zhimin</creatorcontrib><creatorcontrib>Ji, Hongxiang</creatorcontrib><creatorcontrib>Zhao, Jun</creatorcontrib><creatorcontrib>Liu, Wenbin</creatorcontrib><creatorcontrib>Li, Zishuai</creatorcontrib><creatorcontrib>Liu, Donghong</creatorcontrib><creatorcontrib>Han, Xue</creatorcontrib><creatorcontrib>Qian, Youwen</creatorcontrib><creatorcontrib>Dong, Hui</creatorcontrib><creatorcontrib>Zhou, Xiong</creatorcontrib><creatorcontrib>Fan, Junyan</creatorcontrib><creatorcontrib>Zhu, Xiaoqiong</creatorcontrib><creatorcontrib>Yin, Jianhua</creatorcontrib><creatorcontrib>Tan, Xiaojie</creatorcontrib><creatorcontrib>Jiang, Dongming</creatorcontrib><creatorcontrib>Yu, Hongping</creatorcontrib><creatorcontrib>Cao, Guangwen</creatorcontrib><title>Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer</title><title>Cellular oncology (Dordrecht)</title><addtitle>Cell Oncol</addtitle><description>Purpose
We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance.
Methods
PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing.
Results
Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days,
p
= 2.28 × 10
−13
). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness– and epithelial–mesenchymal transition (EMT)–related gene sets were found to be upregulated, whereas liver development– and liver specific molecule–related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis.
Conclusions
HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC.</description><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Drug resistance</subject><subject>Drug screening</subject><subject>Gene expression</subject><subject>Hepatocellular carcinoma</subject><subject>Kinases</subject><subject>Liver cancer</subject><subject>Mesenchyme</subject><subject>Oncology</subject><subject>Organoids</subject><subject>Original Article</subject><subject>Pathology</subject><subject>Patients</subject><subject>Signal transduction</subject><subject>TOR protein</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>2211-3428</issn><issn>2211-3436</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp90U9LwzAYBvAiCg7dF_AU8OLBapo_TXeUoU4YeNFzyJI3NaNLtqQV9u3N7FDwYCAkh9_zkvAUxVWF7yqMxX2qKMOkxCRvLLAo6UkxIaSqSspoffpzJ815MU1pjfNidVXzelKEBfQQQwseXL-_Rc5_QATfI-UNUno3uAgGmTi0KEJyqVdeQ1Zoq3qXXWkgus9MQmyVD86gTTDQJRQs2ka3UXGPugwi0odkvCzOrOoSTI_nRfH-9Pg2X5TL1-eX-cOy1JSTvhSYCGyFVVQwjHXT4NWKcGOIog2zRGPBVG2A0aYhjM-YtVxxMYOa81pbpuhFcTPO3cawGyD1cuOShq5THsKQZB4vGsErzjO9_kPXYYg-vy4rUmPGOCNZkVHpGFKKYOXxe7LC8lCDHGuQuQb5XYOkOUTHUMrYtxB_R_-T-gID-Yqj</recordid><startdate>20221001</startdate><enddate>20221001</enddate><creator>Xian, Linfeng</creator><creator>Zhao, Pei</creator><creator>Chen, Xi</creator><creator>Wei, Zhimin</creator><creator>Ji, Hongxiang</creator><creator>Zhao, Jun</creator><creator>Liu, Wenbin</creator><creator>Li, Zishuai</creator><creator>Liu, Donghong</creator><creator>Han, Xue</creator><creator>Qian, Youwen</creator><creator>Dong, Hui</creator><creator>Zhou, Xiong</creator><creator>Fan, Junyan</creator><creator>Zhu, Xiaoqiong</creator><creator>Yin, Jianhua</creator><creator>Tan, Xiaojie</creator><creator>Jiang, Dongming</creator><creator>Yu, Hongping</creator><creator>Cao, Guangwen</creator><general>Springer Netherlands</general><general>Springer Nature B.V</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8094-1278</orcidid></search><sort><creationdate>20221001</creationdate><title>Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer</title><author>Xian, Linfeng ; Zhao, Pei ; Chen, Xi ; Wei, Zhimin ; Ji, Hongxiang ; Zhao, Jun ; Liu, Wenbin ; Li, Zishuai ; Liu, Donghong ; Han, Xue ; Qian, Youwen ; Dong, Hui ; Zhou, Xiong ; Fan, Junyan ; Zhu, Xiaoqiong ; Yin, Jianhua ; Tan, Xiaojie ; Jiang, Dongming ; Yu, Hongping ; Cao, Guangwen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c352t-70270f7fa37400c880bb25dd2a384f2c074a6de438824594ff5a579e6556cf4a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Drug resistance</topic><topic>Drug screening</topic><topic>Gene expression</topic><topic>Hepatocellular carcinoma</topic><topic>Kinases</topic><topic>Liver cancer</topic><topic>Mesenchyme</topic><topic>Oncology</topic><topic>Organoids</topic><topic>Original Article</topic><topic>Pathology</topic><topic>Patients</topic><topic>Signal transduction</topic><topic>TOR protein</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>online_resources</toplevel><creatorcontrib>Xian, Linfeng</creatorcontrib><creatorcontrib>Zhao, Pei</creatorcontrib><creatorcontrib>Chen, Xi</creatorcontrib><creatorcontrib>Wei, Zhimin</creatorcontrib><creatorcontrib>Ji, Hongxiang</creatorcontrib><creatorcontrib>Zhao, Jun</creatorcontrib><creatorcontrib>Liu, Wenbin</creatorcontrib><creatorcontrib>Li, Zishuai</creatorcontrib><creatorcontrib>Liu, Donghong</creatorcontrib><creatorcontrib>Han, Xue</creatorcontrib><creatorcontrib>Qian, Youwen</creatorcontrib><creatorcontrib>Dong, Hui</creatorcontrib><creatorcontrib>Zhou, Xiong</creatorcontrib><creatorcontrib>Fan, Junyan</creatorcontrib><creatorcontrib>Zhu, Xiaoqiong</creatorcontrib><creatorcontrib>Yin, Jianhua</creatorcontrib><creatorcontrib>Tan, Xiaojie</creatorcontrib><creatorcontrib>Jiang, Dongming</creatorcontrib><creatorcontrib>Yu, Hongping</creatorcontrib><creatorcontrib>Cao, Guangwen</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cellular oncology (Dordrecht)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xian, Linfeng</au><au>Zhao, Pei</au><au>Chen, Xi</au><au>Wei, Zhimin</au><au>Ji, Hongxiang</au><au>Zhao, Jun</au><au>Liu, Wenbin</au><au>Li, Zishuai</au><au>Liu, Donghong</au><au>Han, Xue</au><au>Qian, Youwen</au><au>Dong, Hui</au><au>Zhou, Xiong</au><au>Fan, Junyan</au><au>Zhu, Xiaoqiong</au><au>Yin, Jianhua</au><au>Tan, Xiaojie</au><au>Jiang, Dongming</au><au>Yu, Hongping</au><au>Cao, Guangwen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer</atitle><jtitle>Cellular oncology (Dordrecht)</jtitle><stitle>Cell Oncol</stitle><date>2022-10-01</date><risdate>2022</risdate><volume>45</volume><issue>5</issue><spage>1019</spage><epage>1036</epage><pages>1019-1036</pages><issn>2211-3428</issn><eissn>2211-3436</eissn><abstract>Purpose
We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance.
Methods
PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing.
Results
Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days,
p
= 2.28 × 10
−13
). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness– and epithelial–mesenchymal transition (EMT)–related gene sets were found to be upregulated, whereas liver development– and liver specific molecule–related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis.
Conclusions
HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><doi>10.1007/s13402-022-00707-3</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-8094-1278</orcidid></addata></record> |
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| subjects | Biomedical and Life Sciences Biomedicine Cancer Research Drug resistance Drug screening Gene expression Hepatocellular carcinoma Kinases Liver cancer Mesenchyme Oncology Organoids Original Article Pathology Patients Signal transduction TOR protein Tumors Xenografts |
| title | Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer |
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