Yuval Kahan Yossef, Liav Sela Peremen, Alona Telerman, Gil Goldinger, Sergey Malitsky, Maxim Itkin, Reut Halperin, Naama Peshes Yaloz, Amit Tirosh
<p>Dear Editor,</p><p>Von Hippel−Lindau protein (pVHL) is a critical factor in the cellular oxygen sensing apparatus. pVHL-deficient tumours are characterized by a pseudohypoxic state and a consequent metabolic shift towards anaerobic metabolism. Based on unbiased metabolic analysis, supported by single-cell transcriptomics analysis, we report a potential tumorigenic role of adenosine in pVHL-deficient pancreatic neuroendocrine tumors (vPNET).</p><p>VHL disease, caused by germline DNA pathogenic variants (PVs) in the <i>VHL</i> gene,<span><sup>1</sup></span> is associated with predisposition for pancreatic neuroendocrine tumours (PNETs); hemangioblastoma(s) of the cerebellum, spine and retina; pheochromocytoma and paraganglioma, and renal cell carcinoma of clear-cell type.<span><sup>1</sup></span></p><p>The pVHL serves as the recognition unit of the ubiquitin system and identifies hypoxia-inducible factor 1α (HIF1α) to promote its degradation.<span><sup>2, 3</sup></span> pVHL-deficient states lead to HIF1α accumulation and pseudohypoxia,<span><sup>4, 5</sup></span> which promotes tumorigenesis and tumour progression and prompts a metabolic shift from oxidative pyruvate breakdown towards anaerobic glucose utilization.<span><sup>2, 6, 7</sup></span></p><p>Somatic <i>VHL</i> PVs are exceedingly rare in sporadic PNET (sPNET).<span><sup>8</sup></span> Hence, we hypothesized that <i>VHL</i> PV alone is insufficient for developing vPNET, and metabolic changes drive tumorigenesis. To elucidate this, we conducted tumour metabolomic profiling, single-cell transcriptomic studies and tissue immunohistochemical characterization of vPNET and sPNET (please see full methods in the Supplementary Material).</p><p>The current work initiated with an unbiased metabolomic analysis to investigate the metabolic environment in patient-derived tissue samples of vPNET and sPNET. Our analysis led to the putative identification of 217 polar metabolites (Supplementary Material) that demonstrated distinct metabolomic signatures and separation of vPNET versus sPNET (Figure 1A). To identify the metabolites that contributed most to the distinction between the groups, we performed a Variable Importance in Projection analysis, in which adenosine monophosphate (AMP) was identified as a dominant metabolite (Figure 1B). As shown in the volcano plot (Figure 1C) and heatmap (Figure 1D), vPNET had a higher representation of AMP as compared with sPNET.</p><p>Other metabolites that were significantly differentially represented between the groups were less likely to be related to PNET tumorigenesis based on the literature review. To independently validate the metabolomics analysis findings, we performed an unbiased snRNA seq analysis. Single-nucleus RNA sequencing was chosen, as it allows single-cell transcriptomic analysis of frozen samples.</p><p>In the snRNA sequencing analysis, 25 982 high-quality cells from two vPNET and five sPNET were identified and analysed. Using canonical correlat
{"title":"Single-cell transcriptomics and metabolomic analysis reveal adenosine-derived metabolites over-representation in pseudohypoxic neuroendocrine tumours","authors":"Yuval Kahan Yossef, Liav Sela Peremen, Alona Telerman, Gil Goldinger, Sergey Malitsky, Maxim Itkin, Reut Halperin, Naama Peshes Yaloz, Amit Tirosh","doi":"10.1002/ctm2.70159","DOIUrl":"https://doi.org/10.1002/ctm2.70159","url":null,"abstract":"<p>Dear Editor,</p><p>Von Hippel−Lindau protein (pVHL) is a critical factor in the cellular oxygen sensing apparatus. pVHL-deficient tumours are characterized by a pseudohypoxic state and a consequent metabolic shift towards anaerobic metabolism. Based on unbiased metabolic analysis, supported by single-cell transcriptomics analysis, we report a potential tumorigenic role of adenosine in pVHL-deficient pancreatic neuroendocrine tumors (vPNET).</p><p>VHL disease, caused by germline DNA pathogenic variants (PVs) in the <i>VHL</i> gene,<span><sup>1</sup></span> is associated with predisposition for pancreatic neuroendocrine tumours (PNETs); hemangioblastoma(s) of the cerebellum, spine and retina; pheochromocytoma and paraganglioma, and renal cell carcinoma of clear-cell type.<span><sup>1</sup></span></p><p>The pVHL serves as the recognition unit of the ubiquitin system and identifies hypoxia-inducible factor 1α (HIF1α) to promote its degradation.<span><sup>2, 3</sup></span> pVHL-deficient states lead to HIF1α accumulation and pseudohypoxia,<span><sup>4, 5</sup></span> which promotes tumorigenesis and tumour progression and prompts a metabolic shift from oxidative pyruvate breakdown towards anaerobic glucose utilization.<span><sup>2, 6, 7</sup></span></p><p>Somatic <i>VHL</i> PVs are exceedingly rare in sporadic PNET (sPNET).<span><sup>8</sup></span> Hence, we hypothesized that <i>VHL</i> PV alone is insufficient for developing vPNET, and metabolic changes drive tumorigenesis. To elucidate this, we conducted tumour metabolomic profiling, single-cell transcriptomic studies and tissue immunohistochemical characterization of vPNET and sPNET (please see full methods in the Supplementary Material).</p><p>The current work initiated with an unbiased metabolomic analysis to investigate the metabolic environment in patient-derived tissue samples of vPNET and sPNET. Our analysis led to the putative identification of 217 polar metabolites (Supplementary Material) that demonstrated distinct metabolomic signatures and separation of vPNET versus sPNET (Figure 1A). To identify the metabolites that contributed most to the distinction between the groups, we performed a Variable Importance in Projection analysis, in which adenosine monophosphate (AMP) was identified as a dominant metabolite (Figure 1B). As shown in the volcano plot (Figure 1C) and heatmap (Figure 1D), vPNET had a higher representation of AMP as compared with sPNET.</p><p>Other metabolites that were significantly differentially represented between the groups were less likely to be related to PNET tumorigenesis based on the literature review. To independently validate the metabolomics analysis findings, we performed an unbiased snRNA seq analysis. Single-nucleus RNA sequencing was chosen, as it allows single-cell transcriptomic analysis of frozen samples.</p><p>In the snRNA sequencing analysis, 25 982 high-quality cells from two vPNET and five sPNET were identified and analysed. Using canonical correlat","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>We present a multi-organ transcriptomic atlas of labour for unprecedented comprehensive profiling of both organ-specific and systemic signalling changes associated with labour across maternal and fetal compartments. Labour signifies the concluding phase of pregnancy. While pregnancy is known to induce pronounced maternal and fetal reprogramming,<span><sup>1</sup></span> specific alteration driven by labour remains elusive. In this context, previous studies have predominantly concentrated on individual organ systems,<span><sup>2</sup></span> limited to gene-level analyses for specific marker gene identification,<span><sup>3</sup></span> and more comprehensive overviews are lacking.</p><p>We surveyed Gene Expression Omnibus for all available transcriptomic datasets across both maternal and fetal compartments to collate a multi-organ transcriptomic atlas, cross-sectionally comparing labour versus non-labour (Supporting Information). The atlas contains 16 datasets, spanning six organ systems (maternal blood, subcutaneous fat, visceral fat, placenta, myometrium and cord blood mononuclear cells [CBMCs]), with 392 samples in total (Figure 1).</p><p>Extensive analyses like gene set enrichment analysis (GSEA) were run, focusing on pathway-level changes during labour. For each organ system, we compared the results from different datasets and compiled the most consistent changes. In maternal blood, labour was linked to upregulation of allograft rejection, tumour necrosis factor (TNF)-NFκB-related, and Myc-related signalling (Figure 1). Myc signals were also enhanced in maternal adipose tissues in labour, accompanied by pronounced metabolic changes like enhanced glycolysis, oxidative phosphorylation (OXPHOS) and fatty acid metabolism (FAM) in both visceral and subcutaneous fat (Figure 1).</p><p>We next probed the organs directly implicated in labour like myometrium and placenta (Figure 1). Similar to adipose tissues, myometrium exhibited increased glycolysis and Myc signalling. TNF and interleukin (IL)-6 signalling were higher, possibly induced by mTORC1 activation. These were consistent across seven myometrial datasets.</p><p>Labor-associated immune activation was also found in the placenta, as TNF signalling was consistently higher (Figure 1), aligned with a previous report.<span><sup>2</sup></span> A published single-cell RNA-seq (scRNA-seq) dataset for placental tissues with/without labour was re-analyzed (Figure 1). As in the original study, eight different cell subsets were identified (endothelial cells, EC; decidual stromal cells, DSC; extravillous trophoblasts, EVT; smooth muscle cells, SMC; dendritic cells, DC; T cells, T; fibroblasts, FB; endometrial cells, EEC). EECs were excluded from downstream analysis due to low cellularity. GSEA found that all cell subsets upregulated the TNF signalling pathway in labour. They also generally displayed more active metabolic profiles, upregulating glycolysis, OXPHOS and FAM. An exception was EVTs, where the
{"title":"Multi-organ transcriptomic atlas reveals hallmarks of labour","authors":"Duan Ni, Ralph Nanan","doi":"10.1002/ctm2.70208","DOIUrl":"https://doi.org/10.1002/ctm2.70208","url":null,"abstract":"<p>We present a multi-organ transcriptomic atlas of labour for unprecedented comprehensive profiling of both organ-specific and systemic signalling changes associated with labour across maternal and fetal compartments. Labour signifies the concluding phase of pregnancy. While pregnancy is known to induce pronounced maternal and fetal reprogramming,<span><sup>1</sup></span> specific alteration driven by labour remains elusive. In this context, previous studies have predominantly concentrated on individual organ systems,<span><sup>2</sup></span> limited to gene-level analyses for specific marker gene identification,<span><sup>3</sup></span> and more comprehensive overviews are lacking.</p><p>We surveyed Gene Expression Omnibus for all available transcriptomic datasets across both maternal and fetal compartments to collate a multi-organ transcriptomic atlas, cross-sectionally comparing labour versus non-labour (Supporting Information). The atlas contains 16 datasets, spanning six organ systems (maternal blood, subcutaneous fat, visceral fat, placenta, myometrium and cord blood mononuclear cells [CBMCs]), with 392 samples in total (Figure 1).</p><p>Extensive analyses like gene set enrichment analysis (GSEA) were run, focusing on pathway-level changes during labour. For each organ system, we compared the results from different datasets and compiled the most consistent changes. In maternal blood, labour was linked to upregulation of allograft rejection, tumour necrosis factor (TNF)-NFκB-related, and Myc-related signalling (Figure 1). Myc signals were also enhanced in maternal adipose tissues in labour, accompanied by pronounced metabolic changes like enhanced glycolysis, oxidative phosphorylation (OXPHOS) and fatty acid metabolism (FAM) in both visceral and subcutaneous fat (Figure 1).</p><p>We next probed the organs directly implicated in labour like myometrium and placenta (Figure 1). Similar to adipose tissues, myometrium exhibited increased glycolysis and Myc signalling. TNF and interleukin (IL)-6 signalling were higher, possibly induced by mTORC1 activation. These were consistent across seven myometrial datasets.</p><p>Labor-associated immune activation was also found in the placenta, as TNF signalling was consistently higher (Figure 1), aligned with a previous report.<span><sup>2</sup></span> A published single-cell RNA-seq (scRNA-seq) dataset for placental tissues with/without labour was re-analyzed (Figure 1). As in the original study, eight different cell subsets were identified (endothelial cells, EC; decidual stromal cells, DSC; extravillous trophoblasts, EVT; smooth muscle cells, SMC; dendritic cells, DC; T cells, T; fibroblasts, FB; endometrial cells, EEC). EECs were excluded from downstream analysis due to low cellularity. GSEA found that all cell subsets upregulated the TNF signalling pathway in labour. They also generally displayed more active metabolic profiles, upregulating glycolysis, OXPHOS and FAM. An exception was EVTs, where the ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ronan J. Kelly, Valsamo Anagnostou, Vincent K. Lam, Ali H. Zaidi
<p>The optimal management of operable oesophageal/GEJ (E/GEJ) cancer has been the subject of much debate with the traditional trimodality approach of chemoradiotherapy followed by surgery as established by the CROSS trial<span><sup>1</sup></span> in 2012 being challenged by the recently presented results of the ESOPEC trial<span><sup>2</sup></span> which demonstrated superiority of the perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) chemotherapy regimen. Unfortunately, ESOPEC a phase III German led study that enrolled patients between 2016 and 2020 did not compare FLOT to the other standard of care which is chemoradiation followed by adjuvant nivolumab. CheckMate 577 a phase III international adjuvant study<span><sup>3</sup></span> published in 2021 investigated the efficacy of the PD-1 inhibitor nivolumab as a systemic agent in an attempt to overcome the challenges posed by utilising radiation sensitising low-dose chemotherapy used in the CROSS regimen. CheckMate 577 demonstrated a doubling in median disease-free survival (mDFS) from 11.0 to 22.4 months (HR 0.69) with the use of adjuvant nivolumab in tumours that had failed to attain a pathological complete response (pCR) post trimodality therapy. mDFS was the primary endpoint of the study but interestingly the secondary endpoint of median distant metastasis-free survival was also increased from 17.6 to 28.3 months (HR 0.74), indicating a systemic effect for PD-1 inhibition above and beyond loco-regional benefits. As is the norm in large adjuvant studies, overall survival (OS) has not been reported as yet requiring a number of years to meet predefined events but challenges in interpretation will exist given the widespread use of immune checkpoint inhibitors (ICIs) in the metastatic setting.<span><sup>4</sup></span> The question therefore remains which is a better approach in operable E/GEJ cancers—perioperative FLOT or trimodality therapy followed by adjuvant nivolumab? In 2025, it may be the wrong question to ask whether chemotherapy or radiation is better, as the answer will vary depending on the biology of an individual's tumour. With the use of precision medicine, we would hope to be able to gain a more nuanced understanding and define an optimal way to select the most appropriate therapeutic options. This approach aims to ensure that patients achieve the best possible results while avoiding over- or under-treatment and undue toxicities.</p><p>The use of circulating tumour DNA (ctDNA) in detecting and tracking minimal residual disease (MRD) may improve upon the use of traditional ypTNM staging and pCR as surrogates for long-term survival.</p><p>In our study published in <i>Nature Medicine</i> in April 2024,<span><sup>5</sup></span> we sought to measure systemic tumour burden kinetics longitudinally using a tumour-agnostic, matched WBC DNA-informed deep sequencing approach coupled with a branched logic to assign variant cellular origin in the pre- and post-operative s
{"title":"The utilisation of ctDNA approaches for residual disease detection during neoadjuvant and perioperative immunotherapy in oesophagogastric cancers","authors":"Ronan J. Kelly, Valsamo Anagnostou, Vincent K. Lam, Ali H. Zaidi","doi":"10.1002/ctm2.70223","DOIUrl":"https://doi.org/10.1002/ctm2.70223","url":null,"abstract":"<p>The optimal management of operable oesophageal/GEJ (E/GEJ) cancer has been the subject of much debate with the traditional trimodality approach of chemoradiotherapy followed by surgery as established by the CROSS trial<span><sup>1</sup></span> in 2012 being challenged by the recently presented results of the ESOPEC trial<span><sup>2</sup></span> which demonstrated superiority of the perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) chemotherapy regimen. Unfortunately, ESOPEC a phase III German led study that enrolled patients between 2016 and 2020 did not compare FLOT to the other standard of care which is chemoradiation followed by adjuvant nivolumab. CheckMate 577 a phase III international adjuvant study<span><sup>3</sup></span> published in 2021 investigated the efficacy of the PD-1 inhibitor nivolumab as a systemic agent in an attempt to overcome the challenges posed by utilising radiation sensitising low-dose chemotherapy used in the CROSS regimen. CheckMate 577 demonstrated a doubling in median disease-free survival (mDFS) from 11.0 to 22.4 months (HR 0.69) with the use of adjuvant nivolumab in tumours that had failed to attain a pathological complete response (pCR) post trimodality therapy. mDFS was the primary endpoint of the study but interestingly the secondary endpoint of median distant metastasis-free survival was also increased from 17.6 to 28.3 months (HR 0.74), indicating a systemic effect for PD-1 inhibition above and beyond loco-regional benefits. As is the norm in large adjuvant studies, overall survival (OS) has not been reported as yet requiring a number of years to meet predefined events but challenges in interpretation will exist given the widespread use of immune checkpoint inhibitors (ICIs) in the metastatic setting.<span><sup>4</sup></span> The question therefore remains which is a better approach in operable E/GEJ cancers—perioperative FLOT or trimodality therapy followed by adjuvant nivolumab? In 2025, it may be the wrong question to ask whether chemotherapy or radiation is better, as the answer will vary depending on the biology of an individual's tumour. With the use of precision medicine, we would hope to be able to gain a more nuanced understanding and define an optimal way to select the most appropriate therapeutic options. This approach aims to ensure that patients achieve the best possible results while avoiding over- or under-treatment and undue toxicities.</p><p>The use of circulating tumour DNA (ctDNA) in detecting and tracking minimal residual disease (MRD) may improve upon the use of traditional ypTNM staging and pCR as surrogates for long-term survival.</p><p>In our study published in <i>Nature Medicine</i> in April 2024,<span><sup>5</sup></span> we sought to measure systemic tumour burden kinetics longitudinally using a tumour-agnostic, matched WBC DNA-informed deep sequencing approach coupled with a branched logic to assign variant cellular origin in the pre- and post-operative s","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lu Z, Zheng S, Liu C, et al. S100A7 as a potential diagnostic andprognostic biomarker of esophageal squamous cellcarcinoma promotes M2 macrophage infiltrationand angiogenesis. Clin Transl Med. 2021;11:e459. doi: 10.1002/ctm2.459
The reason for the correction:
We proofread the entire article and found that the Western Blot band of the p65 protein in the S100A7 siRNA silencing group in Figure 3H on page 6 accidentally used the same band as the p65 protein in the S100A7 siRNA silencing group in Figure 3G during the editing process.
The western Blot band of p65 protein in the S100A7 siRNA silencing group in Figure 3H that needs errata is marked with a red block below.
{"title":"Erratum for the “S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis” by Zhiliang Lu et al.","authors":"","doi":"10.1002/ctm2.70222","DOIUrl":"https://doi.org/10.1002/ctm2.70222","url":null,"abstract":"<p>Lu Z, Zheng S, Liu C, et al. S100A7 as a potential diagnostic andprognostic biomarker of esophageal squamous cellcarcinoma promotes M2 macrophage infiltrationand angiogenesis. <i>Clin Transl Med</i>. 2021;11:e459. doi: 10.1002/ctm2.459</p><p>The reason for the correction:</p><p>We proofread the entire article and found that the Western Blot band of the p65 protein in the S100A7 siRNA silencing group in Figure 3H on page 6 accidentally used the same band as the p65 protein in the S100A7 siRNA silencing group in Figure 3G during the editing process.</p><p>The western Blot band of p65 protein in the S100A7 siRNA silencing group in Figure 3H that needs errata is marked with a red block below.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Abnormal metabolism is a biological hallmark of cancer and represents critical targets for therapeutic intervention, as it unveils potential vulnerabilities for treatment.<span><sup>1</sup></span> To sustain continuous proliferation and metastasis, tumour cells undergo several metabolic adaptations to cope with the nutrient-deficient microenvironment. Recent advancements have demonstrated the successful translation of identified metabolic dysregulations in cancer cells into FDA-approved metabolic inhibitors. Currently, several metabolic regulators are being developed or are undergoing clinical trials for the treatment of various cancers, such as nucleotide synthesis inhibitors (e.g. aminopterin, methotrexate and pemetrexed), indoleamine 2,3-dioxygenase 1 inhibitors (e.g. linrodostat and KHK2455), isocitrate dehydrogenases inhibitors (e.g. ivosidenib and enasidenib), glutaminase inhibitors (e.g. telaglenastat and telaglenastat), lactate efflux inhibitors (e.g. AZD3965), tyrosine mimetics (e.g. racemetyrosine), and so on.<span><sup>2, 3</sup></span> However, despite significant advancements in the development of drugs targeting cancer genomic alterations and the tumour microenvironment, the progress in targeting cancer metabolism—particularly non-nucleotide metabolism—remains in its nascent stages. A major challenge in targeting cancer metabolism for therapy lies in achieving effective antitumour effects while minimizing toxicity to normal cells, as many metabolic pathways essential for tumour cell survival are also shared by normal cells, resulting in a narrow therapeutic window and potential for significant toxicity.<span><sup>4</sup></span></p><p>Xanthine oxidoreductase (XOR), a key enzyme in purine catabolism containing redox-active molybdenum (Mo) and iron (Fe) centres, catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA).<span><sup>5</sup></span> Its expression and activity are significantly reduced in tumour tissues from liver, breast, gastrointestinal, colorectal, ovarian and non-small cell lung cancers, with low XOR levels strongly associated with poor prognosis and recurrence.<span><sup>6, 7</sup></span> Moreover, the documented immunosuppressive properties of certain xanthine derivatives<span><sup>8</sup></span> and the notable role of UA in enhancing anti-tumour immunity<span><sup>9</sup></span> underscore the pivotal relevance of XOR in cancer research, suggesting its potential as both a therapeutic target and a mediator of immune responses. Leveraging this insight, we engineered FeMoO<sub>4</sub> nanocatalysts, an artificial metabzyme graced with Fe<sup>2+</sup> and tetrahedral Mo<sup>4+</sup> active centres, to seamlessly simulate XOR's catalytic essence.<span><sup>10</sup></span> Upon entering tumour cells with low XOR levels and elevated xanthine substrates, the FeMoO<sub>4</sub> metabzyme efficiently catalyses the conversion of xanthine into excess UA. Interestingly, UA metabolite, in turn, trigger
{"title":"Artificial metabzyme-driven metabolic reprogramming and precision oncology","authors":"Xi Hu, Daishun Ling","doi":"10.1002/ctm2.70215","DOIUrl":"10.1002/ctm2.70215","url":null,"abstract":"<p>Abnormal metabolism is a biological hallmark of cancer and represents critical targets for therapeutic intervention, as it unveils potential vulnerabilities for treatment.<span><sup>1</sup></span> To sustain continuous proliferation and metastasis, tumour cells undergo several metabolic adaptations to cope with the nutrient-deficient microenvironment. Recent advancements have demonstrated the successful translation of identified metabolic dysregulations in cancer cells into FDA-approved metabolic inhibitors. Currently, several metabolic regulators are being developed or are undergoing clinical trials for the treatment of various cancers, such as nucleotide synthesis inhibitors (e.g. aminopterin, methotrexate and pemetrexed), indoleamine 2,3-dioxygenase 1 inhibitors (e.g. linrodostat and KHK2455), isocitrate dehydrogenases inhibitors (e.g. ivosidenib and enasidenib), glutaminase inhibitors (e.g. telaglenastat and telaglenastat), lactate efflux inhibitors (e.g. AZD3965), tyrosine mimetics (e.g. racemetyrosine), and so on.<span><sup>2, 3</sup></span> However, despite significant advancements in the development of drugs targeting cancer genomic alterations and the tumour microenvironment, the progress in targeting cancer metabolism—particularly non-nucleotide metabolism—remains in its nascent stages. A major challenge in targeting cancer metabolism for therapy lies in achieving effective antitumour effects while minimizing toxicity to normal cells, as many metabolic pathways essential for tumour cell survival are also shared by normal cells, resulting in a narrow therapeutic window and potential for significant toxicity.<span><sup>4</sup></span></p><p>Xanthine oxidoreductase (XOR), a key enzyme in purine catabolism containing redox-active molybdenum (Mo) and iron (Fe) centres, catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA).<span><sup>5</sup></span> Its expression and activity are significantly reduced in tumour tissues from liver, breast, gastrointestinal, colorectal, ovarian and non-small cell lung cancers, with low XOR levels strongly associated with poor prognosis and recurrence.<span><sup>6, 7</sup></span> Moreover, the documented immunosuppressive properties of certain xanthine derivatives<span><sup>8</sup></span> and the notable role of UA in enhancing anti-tumour immunity<span><sup>9</sup></span> underscore the pivotal relevance of XOR in cancer research, suggesting its potential as both a therapeutic target and a mediator of immune responses. Leveraging this insight, we engineered FeMoO<sub>4</sub> nanocatalysts, an artificial metabzyme graced with Fe<sup>2+</sup> and tetrahedral Mo<sup>4+</sup> active centres, to seamlessly simulate XOR's catalytic essence.<span><sup>10</sup></span> Upon entering tumour cells with low XOR levels and elevated xanthine substrates, the FeMoO<sub>4</sub> metabzyme efficiently catalyses the conversion of xanthine into excess UA. Interestingly, UA metabolite, in turn, trigger","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}