Pub Date : 2025-01-01Epub Date: 2024-10-04DOI: 10.1002/1878-0261.13722
Sara Giovannini, Yanan Li, Rosalba Pecorari, Claudia Fierro, Claudia Fiorilli, Federica Corigliano, Valeria Moriconi, Ji Zhou, Anna De Antoni, Artem Smirnov, Sara Rinalducci, Anna Maria Timperio, Massimiliano Agostini, Jinping Zhang, Yufang Shi, Eleonora Candi, Gerry Melino, Francesca Bernassola
The HECT-type E3 ubiquitin WWP1 (also known as NEDD4-like E3 ubiquitin-protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells. WWP1 overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white blood cells) and counteracts apoptotic cell death and differentiation. In an effort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin-interacting protein (TXNIP)-mediated reactive oxygen species (ROS) production in AML cells. TXNIP inhibits the disulfide reductase enzymatic activity of thioredoxin (Trx), impairing its antioxidant function and, ultimately, leading to the disruption of cellular redox homeostasis. In addition, TXNIP restricts cell growth and survival by blocking glucose uptake and metabolism. Here, we found that WWP1 directly interacts with TXNIP, thus promoting its ubiquitin-dependent proteasomal proteolysis. As a result, accumulation of TXNIP in response to WWP1 inactivation in AML blasts reduces Trx activity and increases ROS production, hence inducing cellular oxidative stress. Increased ROS generation in WWP1-depleted cells culminates in DNA strand breaks and subsequent apoptosis. Coherently with TXNIP stabilization following WWP1 inactivation, we also observed an impairment of both glucose up-take and consumption. Hence, a contribution to the increased cell death observed in WWP1-depleted cells also possibly arises from the attenuation of glucose up-take and glycolytic flux resulting from TXNIP accumulation. Future studies are needed to establish whether TXNIP-dependent deregulation of redox homeostasis in WWP1-overexpressing blasts may affect the response of leukemic cells to chemotherapeutic drugs.
{"title":"Thioredoxin-interacting protein (TXNIP) is a substrate of the NEDD4-like E3 ubiquitin-protein ligase WWP1 in cellular redox state regulation of acute myeloid leukemia cells.","authors":"Sara Giovannini, Yanan Li, Rosalba Pecorari, Claudia Fierro, Claudia Fiorilli, Federica Corigliano, Valeria Moriconi, Ji Zhou, Anna De Antoni, Artem Smirnov, Sara Rinalducci, Anna Maria Timperio, Massimiliano Agostini, Jinping Zhang, Yufang Shi, Eleonora Candi, Gerry Melino, Francesca Bernassola","doi":"10.1002/1878-0261.13722","DOIUrl":"10.1002/1878-0261.13722","url":null,"abstract":"<p><p>The HECT-type E3 ubiquitin WWP1 (also known as NEDD4-like E3 ubiquitin-protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells. WWP1 overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white blood cells) and counteracts apoptotic cell death and differentiation. In an effort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin-interacting protein (TXNIP)-mediated reactive oxygen species (ROS) production in AML cells. TXNIP inhibits the disulfide reductase enzymatic activity of thioredoxin (Trx), impairing its antioxidant function and, ultimately, leading to the disruption of cellular redox homeostasis. In addition, TXNIP restricts cell growth and survival by blocking glucose uptake and metabolism. Here, we found that WWP1 directly interacts with TXNIP, thus promoting its ubiquitin-dependent proteasomal proteolysis. As a result, accumulation of TXNIP in response to WWP1 inactivation in AML blasts reduces Trx activity and increases ROS production, hence inducing cellular oxidative stress. Increased ROS generation in WWP1-depleted cells culminates in DNA strand breaks and subsequent apoptosis. Coherently with TXNIP stabilization following WWP1 inactivation, we also observed an impairment of both glucose up-take and consumption. Hence, a contribution to the increased cell death observed in WWP1-depleted cells also possibly arises from the attenuation of glucose up-take and glycolytic flux resulting from TXNIP accumulation. Future studies are needed to establish whether TXNIP-dependent deregulation of redox homeostasis in WWP1-overexpressing blasts may affect the response of leukemic cells to chemotherapeutic drugs.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"133-150"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-03DOI: 10.1002/1878-0261.13775
Retraction: H. Zhang, T. Liu, S. Yi, L. Gu, and M. Zhou, "Targeting MYCN IRES in MYCN-amplified Neuroblastoma With Mir-375 Inhibits Tumor Growth and Sensitizes Tumor Cells to Radiation," Molecular Oncology 9, no. 7 (2015): 1301-1311, https://doi.org/10.1016/j.molonc.2015.03.005. The above article, published online on 24 March 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Kevin Ryan; FEBS Press; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate image section duplications within the article (Figure 5B) and between this (Figures 3B and 4B) and another article published by the same group of authors in a different scientific context. The authors were unable to provide a satisfactory explanation and the original raw data, which has led the editors to lose confidence in the data presented. Therefore, the editors consider the conclusions substantially compromised and are retracting the paper.
{"title":"RETRACTION: Targeting MYCN IRES in MYCN-amplified Neuroblastoma With Mir-375 Inhibits Tumor Growth and Sensitizes Tumor Cells to Radiation.","authors":"","doi":"10.1002/1878-0261.13775","DOIUrl":"10.1002/1878-0261.13775","url":null,"abstract":"<p><strong>Retraction: </strong>H. Zhang, T. Liu, S. Yi, L. Gu, and M. Zhou, \"Targeting MYCN IRES in MYCN-amplified Neuroblastoma With Mir-375 Inhibits Tumor Growth and Sensitizes Tumor Cells to Radiation,\" Molecular Oncology 9, no. 7 (2015): 1301-1311, https://doi.org/10.1016/j.molonc.2015.03.005. The above article, published online on 24 March 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Kevin Ryan; FEBS Press; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate image section duplications within the article (Figure 5B) and between this (Figures 3B and 4B) and another article published by the same group of authors in a different scientific context. The authors were unable to provide a satisfactory explanation and the original raw data, which has led the editors to lose confidence in the data presented. Therefore, the editors consider the conclusions substantially compromised and are retracting the paper.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"261"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-09-06DOI: 10.1002/1878-0261.13708
Isabelle Neefs, Nele De Meulenaere, Thomas Vanpoucke, Janah Vandenhoeck, Dieter Peeters, Marc Peeters, Guy Van Camp, Ken Op de Beeck
DNA methylation biomarkers have emerged as promising tools for cancer detection. Common methylation patterns across tumor types allow multi-cancer detection. Droplet digital PCR (ddPCR) has gained considerable attention for methylation detection. However, multi-cancer detection using multiple targets in ddPCR has never been performed before. Therefore, we developed a multiplex ddPCR assay for multi-cancer detection. Based on previous data analyses using The Cancer Genome Atlas (TCGA), we selected differentially methylated targets for eight frequent tumor types (lung, breast, colorectal, prostate, pancreatic, head and neck, liver, and esophageal cancer). Three targets were validated using ddPCR in 103 tumor and 109 normal adjacent fresh frozen samples. Two distinct ddPCR assays were successfully developed. Output data from both assays is combined to obtain a read-out from the three targets together. Our overall ddPCR assay has a cross-validated area under the curve (cvAUC) of 0.948. Performance between distinct cancer types varies, with sensitivities ranging from 53.8% to 100% and specificities ranging from 80% to 100%. Compared to previously published single-target parameters, we show that combining targets can drastically increase sensitivity and specificity, while lowering DNA input. In conclusion, we are the first to report a multi-cancer methylation ddPCR assay, which allows for highly accurate tumor predictions.
{"title":"Simultaneous detection of eight cancer types using a multiplex droplet digital PCR assay.","authors":"Isabelle Neefs, Nele De Meulenaere, Thomas Vanpoucke, Janah Vandenhoeck, Dieter Peeters, Marc Peeters, Guy Van Camp, Ken Op de Beeck","doi":"10.1002/1878-0261.13708","DOIUrl":"10.1002/1878-0261.13708","url":null,"abstract":"<p><p>DNA methylation biomarkers have emerged as promising tools for cancer detection. Common methylation patterns across tumor types allow multi-cancer detection. Droplet digital PCR (ddPCR) has gained considerable attention for methylation detection. However, multi-cancer detection using multiple targets in ddPCR has never been performed before. Therefore, we developed a multiplex ddPCR assay for multi-cancer detection. Based on previous data analyses using The Cancer Genome Atlas (TCGA), we selected differentially methylated targets for eight frequent tumor types (lung, breast, colorectal, prostate, pancreatic, head and neck, liver, and esophageal cancer). Three targets were validated using ddPCR in 103 tumor and 109 normal adjacent fresh frozen samples. Two distinct ddPCR assays were successfully developed. Output data from both assays is combined to obtain a read-out from the three targets together. Our overall ddPCR assay has a cross-validated area under the curve (cvAUC) of 0.948. Performance between distinct cancer types varies, with sensitivities ranging from 53.8% to 100% and specificities ranging from 80% to 100%. Compared to previously published single-target parameters, we show that combining targets can drastically increase sensitivity and specificity, while lowering DNA input. In conclusion, we are the first to report a multi-cancer methylation ddPCR assay, which allows for highly accurate tumor predictions.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"188-203"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-09-26DOI: 10.1002/1878-0261.13731
Zhong Fan, Yanan Jiang, Xiaotian Zhang
Precise regulation of gene expression is essential for proper development and the maintenance of homeostasis in organisms. Studies have shown that some transcriptional regulatory proteins influence gene expression through the formation of dynamic, locally concentrated assemblies known as condensates, while dysregulation of transcriptional condensates was associated with several cancers, such as Ewing sarcoma and AML [Wang Y et al. (2023) Nat Chem Biol 19, 1223-1234; Chandra B et al. (2022) Cancer Discov 12, 1152-1169]. Mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL) have been shown to form discrete condensates at endogenous genomic targets, but it remains unclear how ENL mutations drive tumorigenesis and whether it is correlated with their condensate formation property. Liu et al. now show, using a conditional knock-in mouse model, that ENL YEATS domain mutation is a bona fide oncogenic driver for AML. This mutant ENL forms condensates in hematopoietic stem/progenitor cells at the genomic loci of key leukemogenic genes, including Meis1 and Hoxa cluster genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Furthermore, they show that small-molecule inhibition of the acetyl-binding activity displaces ENL mutant condensates from oncogenic target loci, and this inhibitor significantly impairs the onset and progression of AML driven by mutant ENL in vivo.
基因表达的精确调控对于生物体的正常发育和维持平衡至关重要。研究表明,一些转录调控蛋白通过形成动态的、局部集中的集合体(称为凝聚体)来影响基因表达,而转录凝聚体的失调与多种癌症有关,如尤文肉瘤和急性髓细胞性白血病[Wang Y et al. (2023) Nat Chem Biol 19, 1223-1234;Chandra B et al. (2022) Cancer Discov 12, 1152-1169]。组蛋白乙酰化 "阅读器 "十一-十九-白血病(ENL)突变已被证明可在内源性基因组靶点形成离散的凝集物,但ENL突变如何驱动肿瘤发生以及是否与其凝集物形成特性相关仍不清楚。Liu等人现在利用条件性基因敲入小鼠模型表明,ENL YEATS结构域突变是急性髓细胞性白血病的真正致癌驱动因子。这种突变的ENL在造血干细胞/祖细胞中关键致白血病基因(包括Meis1和Hoxa簇基因)的基因组位点上形成凝集物,通过诱变破坏凝集物的形成会损害其染色质和致癌功能。此外,他们还发现,抑制乙酰结合活性的小分子抑制剂可将ENL突变凝集素从致癌靶基因座上置换下来,这种抑制剂可显著抑制突变ENL驱动的AML在体内的发生和发展。
{"title":"ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis.","authors":"Zhong Fan, Yanan Jiang, Xiaotian Zhang","doi":"10.1002/1878-0261.13731","DOIUrl":"10.1002/1878-0261.13731","url":null,"abstract":"<p><p>Precise regulation of gene expression is essential for proper development and the maintenance of homeostasis in organisms. Studies have shown that some transcriptional regulatory proteins influence gene expression through the formation of dynamic, locally concentrated assemblies known as condensates, while dysregulation of transcriptional condensates was associated with several cancers, such as Ewing sarcoma and AML [Wang Y et al. (2023) Nat Chem Biol 19, 1223-1234; Chandra B et al. (2022) Cancer Discov 12, 1152-1169]. Mutations in the histone acetylation \"reader\" eleven-nineteen-leukemia (ENL) have been shown to form discrete condensates at endogenous genomic targets, but it remains unclear how ENL mutations drive tumorigenesis and whether it is correlated with their condensate formation property. Liu et al. now show, using a conditional knock-in mouse model, that ENL YEATS domain mutation is a bona fide oncogenic driver for AML. This mutant ENL forms condensates in hematopoietic stem/progenitor cells at the genomic loci of key leukemogenic genes, including Meis1 and Hoxa cluster genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Furthermore, they show that small-molecule inhibition of the acetyl-binding activity displaces ENL mutant condensates from oncogenic target loci, and this inhibitor significantly impairs the onset and progression of AML driven by mutant ENL in vivo.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"7-10"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-11-27DOI: 10.1002/1878-0261.13777
Retraction: Y.-J. Li, Z. Yang, Y.-Y. Wang, and Y. Wang, "Long Noncoding RNA ZNF667-AS1 Reduces Tumor Invasion and Metastasis in Cervical Cancer by Counteracting Microrna-93-3p-Dependent PEG3 Downregulation," Molecular Oncology 13, no. 11 (2019): 2375-2392, https://doi.org/10.1002/1878-0261.12565. The above article, published online on 17 October 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Kevin Ryan; FEBS Press; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed implausible Western blot data (Figures 5B, L, G and Q), and an image duplication in Figure 6B. The authors' failure to respond with the original raw data has led the editors to lose confidence in the data presented. Therefore, the editors consider the conclusions substantially compromised and are retracting the paper.
撤回:Li Y-J, Yang Z, Wang Y-Y, Wang Y.长非编码RNA ZNF667-AS1通过对抗microRNA-93-3p依赖的PEG3下调减少宫颈癌的肿瘤侵袭和转移Mol Oncol.2019;13(11):2375-2392. https://doi.org/10.1002/1878-0261.12565 上述文章于2019年10月17日在线发表于Wiley Online Library (wileyonlinelibrary.com),经期刊主编Kevin Ryan、FEBS Press和John Wiley & Sons Ltd.协议撤回。在对第三方提出的疑虑进行调查后,作者同意撤稿。第三方提出的疑虑揭示了难以置信的 Western 印迹数据(图 5B,L,G,Q)和图 6B 中的图像重复。由于作者未能提供原始数据,编辑对所提供的数据失去了信心。因此,编辑认为该论文的结论大打折扣,并撤回该论文。
{"title":"RETRACTION: Long Noncoding RNA ZNF667-AS1 Reduces Tumor Invasion and Metastasis in Cervical Cancer by Counteracting Microrna-93-3p-Dependent PEG3 Downregulation.","authors":"","doi":"10.1002/1878-0261.13777","DOIUrl":"10.1002/1878-0261.13777","url":null,"abstract":"<p><strong>Retraction: </strong>Y.-J. Li, Z. Yang, Y.-Y. Wang, and Y. Wang, \"Long Noncoding RNA ZNF667-AS1 Reduces Tumor Invasion and Metastasis in Cervical Cancer by Counteracting Microrna-93-3p-Dependent PEG3 Downregulation,\" Molecular Oncology 13, no. 11 (2019): 2375-2392, https://doi.org/10.1002/1878-0261.12565. The above article, published online on 17 October 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Kevin Ryan; FEBS Press; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed implausible Western blot data (Figures 5B, L, G and Q), and an image duplication in Figure 6B. The authors' failure to respond with the original raw data has led the editors to lose confidence in the data presented. Therefore, the editors consider the conclusions substantially compromised and are retracting the paper.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"263"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-08-26DOI: 10.1002/1878-0261.13721
Nora Hase, Danny Misiak, Helge Taubert, Stefan Hüttelmaier, Michael Gekle, Marcel Köhn
Renowned as the predominant form of kidney cancer, clear cell renal cell carcinoma (ccRCC) exhibits susceptibility to immunotherapies due to its specific expression profile as well as notable immune cell infiltration. Despite this, effectively treating metastatic ccRCC remains a significant challenge, necessitating a more profound comprehension of the underlying molecular mechanisms governing its progression. Here, we unveil that the enhanced expression of the RNA-binding protein DNA dC → dU-editing enzyme APOBEC-3C (APOBEC3C; also known as A3C) in ccRCC tissue and ccRCC-derived cell lines serves as a catalyst for tumor growth by amplifying nuclear factor-kappa B (NF-κB) activity. By employing RNA-sequencing and cell-based assays in ccRCC-derived cell lines, we determined that A3C is a stress-responsive factor and crucial for cell survival. Furthermore, we identified that A3C binds and potentially stabilizes messenger RNAs (mRNAs) encoding positive regulators of the NF-κB pathway. Upon A3C depletion, essential subunits of the NF-κB family are abnormally restrained in the cytoplasm, leading to deregulation of NF-κB target genes. Our study illuminates the pivotal role of A3C in promoting ccRCC tumor development, positioning it as a prospective target for future therapeutic strategies.
{"title":"APOBEC3C-mediated NF-κB activation enhances clear cell renal cell carcinoma progression.","authors":"Nora Hase, Danny Misiak, Helge Taubert, Stefan Hüttelmaier, Michael Gekle, Marcel Köhn","doi":"10.1002/1878-0261.13721","DOIUrl":"10.1002/1878-0261.13721","url":null,"abstract":"<p><p>Renowned as the predominant form of kidney cancer, clear cell renal cell carcinoma (ccRCC) exhibits susceptibility to immunotherapies due to its specific expression profile as well as notable immune cell infiltration. Despite this, effectively treating metastatic ccRCC remains a significant challenge, necessitating a more profound comprehension of the underlying molecular mechanisms governing its progression. Here, we unveil that the enhanced expression of the RNA-binding protein DNA dC → dU-editing enzyme APOBEC-3C (APOBEC3C; also known as A3C) in ccRCC tissue and ccRCC-derived cell lines serves as a catalyst for tumor growth by amplifying nuclear factor-kappa B (NF-κB) activity. By employing RNA-sequencing and cell-based assays in ccRCC-derived cell lines, we determined that A3C is a stress-responsive factor and crucial for cell survival. Furthermore, we identified that A3C binds and potentially stabilizes messenger RNAs (mRNAs) encoding positive regulators of the NF-κB pathway. Upon A3C depletion, essential subunits of the NF-κB family are abnormally restrained in the cytoplasm, leading to deregulation of NF-κB target genes. Our study illuminates the pivotal role of A3C in promoting ccRCC tumor development, positioning it as a prospective target for future therapeutic strategies.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"114-132"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-10-18DOI: 10.1002/1878-0261.13753
Elisa Oricchio
The ability of cancer cells to change and adapt poses a critical challenge to identifying curative solutions. Tumor evolution has been extensively studied from a genetic perspective, to guide clinicians in selecting the most appropriate therapeutic option based on a patient's mutational profile. However, several studies reported that tumors can evolve toward more aggressive stages or become resistant to therapies without changing their genetic makeup. Indeed, several cell-intrinsic and cell-extrinsic mechanisms contribute to tumor evolution. In this viewpoint, I focus on how chromatin, epigenetic, and transcriptional changes contribute to tumor evolution, allowing cancer cells to transition to different cell states and bypass response to therapies. Although tumor nongenetic evolution is harder to trace and predict, understanding its principles might open new therapeutic opportunities.
{"title":"Nongenetic evolution of the tumor: from challenges to new therapeutic opportunities.","authors":"Elisa Oricchio","doi":"10.1002/1878-0261.13753","DOIUrl":"10.1002/1878-0261.13753","url":null,"abstract":"<p><p>The ability of cancer cells to change and adapt poses a critical challenge to identifying curative solutions. Tumor evolution has been extensively studied from a genetic perspective, to guide clinicians in selecting the most appropriate therapeutic option based on a patient's mutational profile. However, several studies reported that tumors can evolve toward more aggressive stages or become resistant to therapies without changing their genetic makeup. Indeed, several cell-intrinsic and cell-extrinsic mechanisms contribute to tumor evolution. In this viewpoint, I focus on how chromatin, epigenetic, and transcriptional changes contribute to tumor evolution, allowing cancer cells to transition to different cell states and bypass response to therapies. Although tumor nongenetic evolution is harder to trace and predict, understanding its principles might open new therapeutic opportunities.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"3-6"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-08-02DOI: 10.1002/1878-0261.13703
Adrish Sen, Salmaan Khan, Stefano Rossetti, Aaron Broege, Ian MacNeil, Ann DeLaForest, Jhomary Molden, Laura Davis, Charles Iversrud, Megan Seibel, Ross Kopher, Stephen Schulz, Lance Laing
Metastatic castration-resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co-targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti-proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM-controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN-dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.
{"title":"Assessments of prostate cancer cell functions highlight differences between a pan-PI3K/mTOR inhibitor, gedatolisib, and single-node inhibitors of the PI3K/AKT/mTOR pathway.","authors":"Adrish Sen, Salmaan Khan, Stefano Rossetti, Aaron Broege, Ian MacNeil, Ann DeLaForest, Jhomary Molden, Laura Davis, Charles Iversrud, Megan Seibel, Ross Kopher, Stephen Schulz, Lance Laing","doi":"10.1002/1878-0261.13703","DOIUrl":"10.1002/1878-0261.13703","url":null,"abstract":"<p><p>Metastatic castration-resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co-targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti-proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM-controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN-dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"225-247"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-08-06DOI: 10.1002/1878-0261.13713
Juliane Albrecht, Mirjam Müller, Völundur Hafstað, Kamila Kaminska, Johan Vallon-Christersson, Gabriella Honeth, Helena Persson
Oestrogen receptor alpha (ER; gene symbol ESR1) is the most important prognostic and treatment-predictive biomarker in breast cancer. Drugs targeting oestrogen and ER for endocrine therapy of breast cancer include aromatase inhibitors, the selective ER modulator tamoxifen and the selective ER degrader fulvestrant. Tumours can develop resistance to endocrine therapy through several mechanisms, which is often linked to altered expression of ER. To investigate the role of promoter methylation in the regulation of ESR1 expression, we used bisulfite sequencing to measure methylation at CpG sites in alternative ER promoter regions for six cell line models of fulvestrant resistance. Both CpG methylation and expression of alternative first exons changed dynamically, with striking differences between cell lines that had stable or unstable resistance upon fulvestrant withdrawal. Methylation at some CpG sites was strongly negatively correlated with expression of specific first exons. In a breast tumour cohort, higher relative expression of upstream alternative first exons was associated with worse prognosis in post-menopausal women with ER-positive tumours who received endocrine therapy.
{"title":"Dynamic methylation and expression of alternative promoters for oestrogen receptor alpha in cell line models of fulvestrant resistance.","authors":"Juliane Albrecht, Mirjam Müller, Völundur Hafstað, Kamila Kaminska, Johan Vallon-Christersson, Gabriella Honeth, Helena Persson","doi":"10.1002/1878-0261.13713","DOIUrl":"10.1002/1878-0261.13713","url":null,"abstract":"<p><p>Oestrogen receptor alpha (ER; gene symbol ESR1) is the most important prognostic and treatment-predictive biomarker in breast cancer. Drugs targeting oestrogen and ER for endocrine therapy of breast cancer include aromatase inhibitors, the selective ER modulator tamoxifen and the selective ER degrader fulvestrant. Tumours can develop resistance to endocrine therapy through several mechanisms, which is often linked to altered expression of ER. To investigate the role of promoter methylation in the regulation of ESR1 expression, we used bisulfite sequencing to measure methylation at CpG sites in alternative ER promoter regions for six cell line models of fulvestrant resistance. Both CpG methylation and expression of alternative first exons changed dynamically, with striking differences between cell lines that had stable or unstable resistance upon fulvestrant withdrawal. Methylation at some CpG sites was strongly negatively correlated with expression of specific first exons. In a breast tumour cohort, higher relative expression of upstream alternative first exons was associated with worse prognosis in post-menopausal women with ER-positive tumours who received endocrine therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"204-224"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-03DOI: 10.1002/1878-0261.13774
Retraction: S. Sinha, R.K. Singh, N. Bhattacharya, N. Mukherjee, S. Ghosh, N. Alam, A. Roy, S. Roychoudhury, and C.K. Panda, "Frequent Alterations of LOH11CR2A, PIG8 and CHEK1 Genes at Chromosomal 11q24.1-24.2 Region in Breast Carcinoma: Clinical and Prognostic Implications," Molecular Oncology 5, no. 5 (2011): 454-464, https://doi.org/10.1016/j.molonc.2011.06.005. The above article, published online on 7 July 2011 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Kevin M. Ryan; the Federation of European Biochemical Societies (FEBS); and John Wiley & Sons Ltd. Following publication, concerns were raised by a third party that portions of Figure 2 were duplicated, and Figures 5A and 5D were duplicated from an earlier publication by this research group. Internal investigation confirmed the duplications in these figures. The retraction has been agreed because of concerns that the images were manipulated, affecting the interpretation of the data and results presented.
引用本文:S. Sinha, R.K. Singh, N. Bhattacharya, N. Mukherjee, S. Ghosh, N. Alam, A. Roy, S. Roychoudhury, C.K. Panda,“乳腺癌11q24.1-24.2区LOH11CR2A、PIG8和CHEK1基因的频繁改变:临床和预后意义”,《分子肿瘤学》第5期,第2期。5 (2011): 454-464, https://doi.org/10.1016/j.molonc.2011.06.005上述文章于2011年7月7日在线发表在Wiley在线图书馆(wileyonlinelibrary.com)上,经该杂志主编Kevin M. Ryan同意撤回;欧洲生化学会联合会(FEBS);及约翰威利父子有限公司。在发表之后,第三方担心图2的部分内容被复制,图5A和图5D是从该研究小组早期发表的文章中复制的。内部调查证实了这些数字的重复。由于担心图像被篡改,影响了对所呈现的数据和结果的解释,因此同意撤稿。
{"title":"RETRACTION: Frequent Alterations of LOH11CR2A, PIG8 and CHEK1 Genes at Chromosomal 11q24.1-24.2 Region in Breast Carcinoma: Clinical and Prognostic Implications.","authors":"","doi":"10.1002/1878-0261.13774","DOIUrl":"10.1002/1878-0261.13774","url":null,"abstract":"<p><strong>Retraction: </strong>S. Sinha, R.K. Singh, N. Bhattacharya, N. Mukherjee, S. Ghosh, N. Alam, A. Roy, S. Roychoudhury, and C.K. Panda, \"Frequent Alterations of LOH11CR2A, PIG8 and CHEK1 Genes at Chromosomal 11q24.1-24.2 Region in Breast Carcinoma: Clinical and Prognostic Implications,\" Molecular Oncology 5, no. 5 (2011): 454-464, https://doi.org/10.1016/j.molonc.2011.06.005. The above article, published online on 7 July 2011 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Kevin M. Ryan; the Federation of European Biochemical Societies (FEBS); and John Wiley & Sons Ltd. Following publication, concerns were raised by a third party that portions of Figure 2 were duplicated, and Figures 5A and 5D were duplicated from an earlier publication by this research group. Internal investigation confirmed the duplications in these figures. The retraction has been agreed because of concerns that the images were manipulated, affecting the interpretation of the data and results presented.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"260"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}