Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1α pathway and does not affect their drug sensitivities
The long culture duration of patient-derived organoids (PDOs) have severely limited their clinical applications. The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7,...
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| Published in: | Cell death discovery 2022-04, Vol.8 (1), p.214-214, Article 214 |
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Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1α pathway and does not affect their drug sensitivities |
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Wang, Zhiwei Yu, Yuanquan Wu, Peiyao Ye, Qinghuang Guo, Yinghao Zhang, Xiaoxiao Xi, Longfu Li, Qi Jin, Yun Zhou, Donger Luo, Yan Peng, Shuyou Li, Jiangtao |
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1-Phosphatidylinositol 3-kinase 5-Fluorouracil AKT protein Cell culture Cell viability Cisplatin Colorectal cancer Drugs Gemcitabine Hypoxia-inducible factors Immune checkpoint Immunosuppressive agents Kinases Lactic acid Leukocytes (mononuclear) Medical prognosis Medicine Organoids Paclitaxel Patients Peripheral blood mononuclear cells Phosphopyruvate hydratase Sensitivity analysis Supplementation Tumors |
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Cell death discovery, 2022-04, Vol.8 (1), p.214-214, Article 214 |
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The long culture duration of patient-derived organoids (PDOs) have severely limited their clinical applications. The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7, Panc02, and RBE cell lines were cultured as organoids in the presence or absence of lactate, and total protein was extracted to measure the expression of α-enolase (ENO1), hypoxia-inducible factor-1α (HIF1α), AKT, and PI3 kinase (PI3K). Thirteen hepatopancreatobiliary tumor specimens were collected during surgical resection and cultured as PDOs with or without L-lactate. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were performed on the original tissues and PDOs to compare their pathological structures, and their genetic profiles were analyzed by whole-exome sequencing (WES). The sensitivity of the PDOs to gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infigratinib, and lenvatinib were evaluated in terms of cell viability. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with PDOs to test the sensitivity of PDOs to tislelizumab. The addition of 20 mM lactate significantly promoted the growth of LM3 and Huh 7 organoids by 217% and 36%, respectively, compared to the control group, and the inhibition of lactate transporter decreased their growth. The HIF1α/ENO1/AKT/PI3K pathway was also activated by lactate. The inhibition of enolase also partly decreased the growth of organoids treated with lactate. Furthermore, 20 mM lactate increased the viability of 9 PDOs from 135% to 317% without affecting their pathological features. The genetic similarity, in terms of single nucleotide variations, insertions, and deletions, between original tissues and lactate-treated PDOs ranged from 83.2% to 94.1%, and that between the untreated and lactate-treated PDOs was at least 93.2%. Furthermore, the addition of lactate did not significantly change the dose-response curves of the PDOs to chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor, especially for the drugs to which the cells were sensitive. Thus, lactate can be added to the culture medium of PDOs to promote their growth without altering their genetic profiles and drug sensitivities. |
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The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7, Panc02, and RBE cell lines were cultured as organoids in the presence or absence of lactate, and total protein was extracted to measure the expression of α-enolase (ENO1), hypoxia-inducible factor-1α (HIF1α), AKT, and PI3 kinase (PI3K). Thirteen hepatopancreatobiliary tumor specimens were collected during surgical resection and cultured as PDOs with or without L-lactate. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were performed on the original tissues and PDOs to compare their pathological structures, and their genetic profiles were analyzed by whole-exome sequencing (WES). The sensitivity of the PDOs to gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infigratinib, and lenvatinib were evaluated in terms of cell viability. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with PDOs to test the sensitivity of PDOs to tislelizumab. The addition of 20 mM lactate significantly promoted the growth of LM3 and Huh 7 organoids by 217% and 36%, respectively, compared to the control group, and the inhibition of lactate transporter decreased their growth. The HIF1α/ENO1/AKT/PI3K pathway was also activated by lactate. The inhibition of enolase also partly decreased the growth of organoids treated with lactate. Furthermore, 20 mM lactate increased the viability of 9 PDOs from 135% to 317% without affecting their pathological features. The genetic similarity, in terms of single nucleotide variations, insertions, and deletions, between original tissues and lactate-treated PDOs ranged from 83.2% to 94.1%, and that between the untreated and lactate-treated PDOs was at least 93.2%. Furthermore, the addition of lactate did not significantly change the dose-response curves of the PDOs to chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor, especially for the drugs to which the cells were sensitive. Thus, lactate can be added to the culture medium of PDOs to promote their growth without altering their genetic profiles and drug sensitivities.</description><identifier>ISSN: 2058-7716</identifier><identifier>EISSN: 2058-7716</identifier><identifier>DOI: 10.1038/s41420-022-01014-4</identifier><identifier>PMID: 35443744</identifier><language>eng</language><publisher>United States: Springer Nature B.V</publisher><subject>1-Phosphatidylinositol 3-kinase ; 5-Fluorouracil ; AKT protein ; Cell culture ; Cell viability ; Cisplatin ; Colorectal cancer ; Drugs ; Gemcitabine ; Hypoxia-inducible factors ; Immune checkpoint ; Immunosuppressive agents ; Kinases ; Lactic acid ; Leukocytes (mononuclear) ; Medical prognosis ; Medicine ; Organoids ; Paclitaxel ; Patients ; Peripheral blood mononuclear cells ; Phosphopyruvate hydratase ; Sensitivity analysis ; Supplementation ; Tumors</subject><ispartof>Cell death discovery, 2022-04, Vol.8 (1), p.214-214, Article 214</ispartof><rights>2022. The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4114-88f2c8e66b41f43c7049cc67fb530a411643671166f90f6eddd12910d0baad803</citedby><cites>FETCH-LOGICAL-c4114-88f2c8e66b41f43c7049cc67fb530a411643671166f90f6eddd12910d0baad803</cites><orcidid>0000-0001-7538-2910</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021221/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021221/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,734,787,791,892,2237,24362,27985,27986,54176,54178</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35443744$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Zhiwei</creatorcontrib><creatorcontrib>Yu, Yuanquan</creatorcontrib><creatorcontrib>Wu, Peiyao</creatorcontrib><creatorcontrib>Ye, Qinghuang</creatorcontrib><creatorcontrib>Guo, Yinghao</creatorcontrib><creatorcontrib>Zhang, Xiaoxiao</creatorcontrib><creatorcontrib>Xi, Longfu</creatorcontrib><creatorcontrib>Li, Qi</creatorcontrib><creatorcontrib>Jin, Yun</creatorcontrib><creatorcontrib>Zhou, Donger</creatorcontrib><creatorcontrib>Luo, Yan</creatorcontrib><creatorcontrib>Peng, Shuyou</creatorcontrib><creatorcontrib>Li, Jiangtao</creatorcontrib><title>Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1α pathway and does not affect their drug sensitivities</title><title>Cell death discovery</title><addtitle>Cell Death Discov</addtitle><description>The long culture duration of patient-derived organoids (PDOs) have severely limited their clinical applications. The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7, Panc02, and RBE cell lines were cultured as organoids in the presence or absence of lactate, and total protein was extracted to measure the expression of α-enolase (ENO1), hypoxia-inducible factor-1α (HIF1α), AKT, and PI3 kinase (PI3K). Thirteen hepatopancreatobiliary tumor specimens were collected during surgical resection and cultured as PDOs with or without L-lactate. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were performed on the original tissues and PDOs to compare their pathological structures, and their genetic profiles were analyzed by whole-exome sequencing (WES). The sensitivity of the PDOs to gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infigratinib, and lenvatinib were evaluated in terms of cell viability. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with PDOs to test the sensitivity of PDOs to tislelizumab. The addition of 20 mM lactate significantly promoted the growth of LM3 and Huh 7 organoids by 217% and 36%, respectively, compared to the control group, and the inhibition of lactate transporter decreased their growth. The HIF1α/ENO1/AKT/PI3K pathway was also activated by lactate. The inhibition of enolase also partly decreased the growth of organoids treated with lactate. Furthermore, 20 mM lactate increased the viability of 9 PDOs from 135% to 317% without affecting their pathological features. The genetic similarity, in terms of single nucleotide variations, insertions, and deletions, between original tissues and lactate-treated PDOs ranged from 83.2% to 94.1%, and that between the untreated and lactate-treated PDOs was at least 93.2%. Furthermore, the addition of lactate did not significantly change the dose-response curves of the PDOs to chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor, especially for the drugs to which the cells were sensitive. Thus, lactate can be added to the culture medium of PDOs to promote their growth without altering their genetic profiles and drug sensitivities.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>5-Fluorouracil</subject><subject>AKT protein</subject><subject>Cell culture</subject><subject>Cell viability</subject><subject>Cisplatin</subject><subject>Colorectal cancer</subject><subject>Drugs</subject><subject>Gemcitabine</subject><subject>Hypoxia-inducible factors</subject><subject>Immune checkpoint</subject><subject>Immunosuppressive agents</subject><subject>Kinases</subject><subject>Lactic acid</subject><subject>Leukocytes (mononuclear)</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Organoids</subject><subject>Paclitaxel</subject><subject>Patients</subject><subject>Peripheral blood mononuclear cells</subject><subject>Phosphopyruvate hydratase</subject><subject>Sensitivity analysis</subject><subject>Supplementation</subject><subject>Tumors</subject><issn>2058-7716</issn><issn>2058-7716</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNpdUs1uEzEQXiEQrUJfgAOyxIXLUv-td3NBQlVLI0X0Amdr1h4njjbrYDup-jh9BF6EZ8LblKrlYHs0_uab-UZfVb1n9DOjojtPkklOa8p5TRllspavqlNOm65uW6ZeP4tPqrOUNpRS1rSy7cTb6kQ0UopWytPqfgkmQ0ayi2EbMiaS10hWMdzmNQmO7CB7HHNtMfoDWhLiCsbgbSKuFJA1FkDYwWgilqD3g4d4R0xJYEzk4IFcfr9h59eLK_bn98S2voU7AqMlNpRmY8gEnEOTp74-Ehv3K5JwTD77QzmY3lVvHAwJzx7fWfXz6vLHxXW9vPm2uPi6rI1kRX7XOW46VKqXzElhWirnxqjW9Y2gUCBKCtWWR7k5dQqttYzPGbW0B7AdFbNqceS1ATZ6F_22KNEBvH5IFOEaYvZmQK1Q8L5pKYLjUjreIfRz0Sqpyt1AU7i-HLl2-36L1pQNRhhekL78Gf1ar8JBzylnnLNC8OmRIIZfe0xZb30yOAwwYtgnzVUjuOqkmub--B90E_ZxLKuaULwVVBTps4ofUSaGlCK6p2EY1ZOh9NFQuhhKPxhKT0Ufnst4KvlnH_EX1FjI9Q</recordid><startdate>20220420</startdate><enddate>20220420</enddate><creator>Wang, Zhiwei</creator><creator>Yu, Yuanquan</creator><creator>Wu, Peiyao</creator><creator>Ye, Qinghuang</creator><creator>Guo, Yinghao</creator><creator>Zhang, Xiaoxiao</creator><creator>Xi, Longfu</creator><creator>Li, Qi</creator><creator>Jin, Yun</creator><creator>Zhou, Donger</creator><creator>Luo, Yan</creator><creator>Peng, Shuyou</creator><creator>Li, Jiangtao</creator><general>Springer Nature B.V</general><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-7538-2910</orcidid></search><sort><creationdate>20220420</creationdate><title>Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1α pathway and does not affect their drug sensitivities</title><author>Wang, Zhiwei ; 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The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7, Panc02, and RBE cell lines were cultured as organoids in the presence or absence of lactate, and total protein was extracted to measure the expression of α-enolase (ENO1), hypoxia-inducible factor-1α (HIF1α), AKT, and PI3 kinase (PI3K). Thirteen hepatopancreatobiliary tumor specimens were collected during surgical resection and cultured as PDOs with or without L-lactate. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were performed on the original tissues and PDOs to compare their pathological structures, and their genetic profiles were analyzed by whole-exome sequencing (WES). The sensitivity of the PDOs to gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infigratinib, and lenvatinib were evaluated in terms of cell viability. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with PDOs to test the sensitivity of PDOs to tislelizumab. The addition of 20 mM lactate significantly promoted the growth of LM3 and Huh 7 organoids by 217% and 36%, respectively, compared to the control group, and the inhibition of lactate transporter decreased their growth. The HIF1α/ENO1/AKT/PI3K pathway was also activated by lactate. The inhibition of enolase also partly decreased the growth of organoids treated with lactate. Furthermore, 20 mM lactate increased the viability of 9 PDOs from 135% to 317% without affecting their pathological features. The genetic similarity, in terms of single nucleotide variations, insertions, and deletions, between original tissues and lactate-treated PDOs ranged from 83.2% to 94.1%, and that between the untreated and lactate-treated PDOs was at least 93.2%. Furthermore, the addition of lactate did not significantly change the dose-response curves of the PDOs to chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor, especially for the drugs to which the cells were sensitive. Thus, lactate can be added to the culture medium of PDOs to promote their growth without altering their genetic profiles and drug sensitivities.</abstract><cop>United States</cop><pub>Springer Nature B.V</pub><pmid>35443744</pmid><doi>10.1038/s41420-022-01014-4</doi><orcidid>https://orcid.org/0000-0001-7538-2910</orcidid><oa>free_for_read</oa></addata></record> |