Jessica C Puzzuoli, Caleb Solivio, Gavin Yuan, Anthony J Rizzo, Mindy K Graham, Larissa Shenker, Will Vista, Adam Gil, Himanshu Singh, Erica Alexander, Adrian Gonzalez-Aguirre, Jonathan Latzman, E Nadia Petre, Hooman Yarmohammadi, Joseph P Erinjeri, Anne Covey, Eric Chan, James Russell, Lisa Bodei, Nitya Raj, Diane Reidy-Lagunes, Christopher M Heaphy, Etay Ziv
{"title":"DAXX/ATRX蛋白表达的缺失导致胰腺神经内分泌肿瘤细胞的缺血抵抗和辐射敏感性，并与经动脉放射栓塞反应的改善有关。","authors":"Jessica C Puzzuoli, Caleb Solivio, Gavin Yuan, Anthony J Rizzo, Mindy K Graham, Larissa Shenker, Will Vista, Adam Gil, Himanshu Singh, Erica Alexander, Adrian Gonzalez-Aguirre, Jonathan Latzman, E Nadia Petre, Hooman Yarmohammadi, Joseph P Erinjeri, Anne Covey, Eric Chan, James Russell, Lisa Bodei, Nitya Raj, Diane Reidy-Lagunes, Christopher M Heaphy, Etay Ziv","doi":"10.1159/000547041","DOIUrl":null,"url":null,"abstract":"<p><strong>Ntroduction: </strong>Metastatic liver pancreatic neuroendocrine tumors (PNETs) can be treated with ischemia-based (trans-arterial embolization [TAE]/trans-arterial chemo-embolization [TACE]) or radiation-based (trans-arterial radioembolization [TARE]). Guidelines for treatment selection are limited. The purpose of this study was to measure the effect of loss of DAXX/ATRX protein expression on ischemia and radiation sensitivity in Bon-1 and QGP-1 cells, and to compare TARE response in PNETs with and without a DAXX/ATRX mutation.</p><p><strong>Methods: </strong>This was a laboratory investigation and retrospective review of an institutional database of TARE-treated PNET patients. Ischemia and radiation sensitivity were tested on Bon-1 and QGP-1 cells and CRISPR-generated DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts. Post-ischemia and post-radiation cell viability, survival fraction and caspase-3 expression were measured. Local progression free survival (LPFS) was measured from time of TARE to local progression or death and estimated using Cox proportional hazards.</p><p><strong>Results: </strong>Post-ischemia DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts had increased cell viability compared with Bon-1 wild type cells (p<0.0001, days 3, 5) and QGP-1 wild type cells (p<0.0001, days 3, 5, 7). Post-radiation C16/C45 and QAX12/QAX24 had decreased survival fraction compared with respective wild type (p<0.0001, all cell lines). C16/C45 had decreased apoptotic activity post-ischemia and increased apoptotic activity post-radiation compared with wild type (p<0.0001, all cell lines). Presence of DAXX/ATRX mutation was associated with longer LPFS after TARE (p<0.001). Median LPFS after TARE was 6 months in wild type compared with 22 months in patients with DAXX/ATRX mutation.</p><p><strong>Conclusion: </strong>Loss of DAXX/ATRX protein expression is associated with ischemia resistance and radiation sensitivity in Bon-1 and QGP-1 cells and longer LPFS after TARE in PNET patients.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-20"},"PeriodicalIF":3.2000,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Loss of DAXX/ATRX protein expression results in ischemia resistance and radiation sensitivity in pancreatic neuroendocrine tumor cells and is associated with improved response to trans-arterial radio-embolization.\",\"authors\":\"Jessica C Puzzuoli, Caleb Solivio, Gavin Yuan, Anthony J Rizzo, Mindy K Graham, Larissa Shenker, Will Vista, Adam Gil, Himanshu Singh, Erica Alexander, Adrian Gonzalez-Aguirre, Jonathan Latzman, E Nadia Petre, Hooman Yarmohammadi, Joseph P Erinjeri, Anne Covey, Eric Chan, James Russell, Lisa Bodei, Nitya Raj, Diane Reidy-Lagunes, Christopher M Heaphy, Etay Ziv\",\"doi\":\"10.1159/000547041\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Ntroduction: </strong>Metastatic liver pancreatic neuroendocrine tumors (PNETs) can be treated with ischemia-based (trans-arterial embolization [TAE]/trans-arterial chemo-embolization [TACE]) or radiation-based (trans-arterial radioembolization [TARE]). Guidelines for treatment selection are limited. The purpose of this study was to measure the effect of loss of DAXX/ATRX protein expression on ischemia and radiation sensitivity in Bon-1 and QGP-1 cells, and to compare TARE response in PNETs with and without a DAXX/ATRX mutation.</p><p><strong>Methods: </strong>This was a laboratory investigation and retrospective review of an institutional database of TARE-treated PNET patients. Ischemia and radiation sensitivity were tested on Bon-1 and QGP-1 cells and CRISPR-generated DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts. Post-ischemia and post-radiation cell viability, survival fraction and caspase-3 expression were measured. Local progression free survival (LPFS) was measured from time of TARE to local progression or death and estimated using Cox proportional hazards.</p><p><strong>Results: </strong>Post-ischemia DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts had increased cell viability compared with Bon-1 wild type cells (p<0.0001, days 3, 5) and QGP-1 wild type cells (p<0.0001, days 3, 5, 7). Post-radiation C16/C45 and QAX12/QAX24 had decreased survival fraction compared with respective wild type (p<0.0001, all cell lines). C16/C45 had decreased apoptotic activity post-ischemia and increased apoptotic activity post-radiation compared with wild type (p<0.0001, all cell lines). Presence of DAXX/ATRX mutation was associated with longer LPFS after TARE (p<0.001). Median LPFS after TARE was 6 months in wild type compared with 22 months in patients with DAXX/ATRX mutation.</p><p><strong>Conclusion: </strong>Loss of DAXX/ATRX protein expression is associated with ischemia resistance and radiation sensitivity in Bon-1 and QGP-1 cells and longer LPFS after TARE in PNET patients.</p>\",\"PeriodicalId\":19117,\"journal\":{\"name\":\"Neuroendocrinology\",\"volume\":\" \",\"pages\":\"1-20\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-07-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuroendocrinology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1159/000547041\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuroendocrinology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1159/000547041","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Loss of DAXX/ATRX protein expression results in ischemia resistance and radiation sensitivity in pancreatic neuroendocrine tumor cells and is associated with improved response to trans-arterial radio-embolization.
Ntroduction: Metastatic liver pancreatic neuroendocrine tumors (PNETs) can be treated with ischemia-based (trans-arterial embolization [TAE]/trans-arterial chemo-embolization [TACE]) or radiation-based (trans-arterial radioembolization [TARE]). Guidelines for treatment selection are limited. The purpose of this study was to measure the effect of loss of DAXX/ATRX protein expression on ischemia and radiation sensitivity in Bon-1 and QGP-1 cells, and to compare TARE response in PNETs with and without a DAXX/ATRX mutation.
Methods: This was a laboratory investigation and retrospective review of an institutional database of TARE-treated PNET patients. Ischemia and radiation sensitivity were tested on Bon-1 and QGP-1 cells and CRISPR-generated DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts. Post-ischemia and post-radiation cell viability, survival fraction and caspase-3 expression were measured. Local progression free survival (LPFS) was measured from time of TARE to local progression or death and estimated using Cox proportional hazards.
Results: Post-ischemia DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts had increased cell viability compared with Bon-1 wild type cells (p<0.0001, days 3, 5) and QGP-1 wild type cells (p<0.0001, days 3, 5, 7). Post-radiation C16/C45 and QAX12/QAX24 had decreased survival fraction compared with respective wild type (p<0.0001, all cell lines). C16/C45 had decreased apoptotic activity post-ischemia and increased apoptotic activity post-radiation compared with wild type (p<0.0001, all cell lines). Presence of DAXX/ATRX mutation was associated with longer LPFS after TARE (p<0.001). Median LPFS after TARE was 6 months in wild type compared with 22 months in patients with DAXX/ATRX mutation.
Conclusion: Loss of DAXX/ATRX protein expression is associated with ischemia resistance and radiation sensitivity in Bon-1 and QGP-1 cells and longer LPFS after TARE in PNET patients.
期刊介绍：
''Neuroendocrinology'' publishes papers reporting original research in basic and clinical neuroendocrinology. The journal explores the complex interactions between neuronal networks and endocrine glands (in some instances also immunecells) in both central and peripheral nervous systems. Original contributions cover all aspects of the field, from molecular and cellular neuroendocrinology, physiology, pharmacology, and the neuroanatomy of neuroendocrine systems to neuroendocrine correlates of behaviour, clinical neuroendocrinology and neuroendocrine cancers. Readers also benefit from reviews by noted experts, which highlight especially active areas of current research, and special focus editions of topical interest.
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