Cell Reports MedicinePub Date : 2024-09-17Epub Date: 2024-08-21DOI: 10.1016/j.xcrm.2024.101694
Qianmin Gao, Yingying Jiang, Dongyang Zhou, Guangfeng Li, Yafei Han, Jingzhi Yang, Ke Xu, Yingying Jing, Long Bai, Zhen Geng, Hao Zhang, Guangyin Zhou, Mengru Zhu, Ning Ji, Ruina Han, Yuanwei Zhang, Zuhao Li, Chuandong Wang, Yan Hu, Hao Shen, Guangchao Wang, Zhongmin Shi, Qinglin Han, Xiao Chen, Jiacan Su
{"title":"Advanced glycation end products mediate biomineralization disorder in diabetic bone disease.","authors":"Qianmin Gao, Yingying Jiang, Dongyang Zhou, Guangfeng Li, Yafei Han, Jingzhi Yang, Ke Xu, Yingying Jing, Long Bai, Zhen Geng, Hao Zhang, Guangyin Zhou, Mengru Zhu, Ning Ji, Ruina Han, Yuanwei Zhang, Zuhao Li, Chuandong Wang, Yan Hu, Hao Shen, Guangchao Wang, Zhongmin Shi, Qinglin Han, Xiao Chen, Jiacan Su","doi":"10.1016/j.xcrm.2024.101694","DOIUrl":"10.1016/j.xcrm.2024.101694","url":null,"abstract":"<p><p>Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035286","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}
Cell Reports MedicinePub Date : 2024-09-17Epub Date: 2024-08-21DOI: 10.1016/j.xcrm.2024.101695
Joseph A Bell, Elizabeth R Davies, Christopher J Brereton, Milica Vukmirovic, James J W Roberts, Kerry Lunn, Leanne Wickens, Franco Conforti, Robert A Ridley, Jessica Ceccato, Lucy N Sayer, David A Johnston, Andres F Vallejo, Aiman Alzetani, Sanjay Jogai, Ben G Marshall, Aurelie Fabre, Luca Richeldi, Phillip D Monk, Paul Skipp, Naftali Kaminski, Emily Offer, Yihua Wang, Donna E Davies, Mark G Jones
{"title":"Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2.","authors":"Joseph A Bell, Elizabeth R Davies, Christopher J Brereton, Milica Vukmirovic, James J W Roberts, Kerry Lunn, Leanne Wickens, Franco Conforti, Robert A Ridley, Jessica Ceccato, Lucy N Sayer, David A Johnston, Andres F Vallejo, Aiman Alzetani, Sanjay Jogai, Ben G Marshall, Aurelie Fabre, Luca Richeldi, Phillip D Monk, Paul Skipp, Naftali Kaminski, Emily Offer, Yihua Wang, Donna E Davies, Mark G Jones","doi":"10.1016/j.xcrm.2024.101695","DOIUrl":"10.1016/j.xcrm.2024.101695","url":null,"abstract":"<p><p>Matrix stiffening by lysyl oxidase-like 2 (LOXL2)-mediated collagen cross-linking is proposed as a core feedforward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested that targeting LOXL2 may not have disease relevance; however, target engagement was not directly evaluated. We compare the spatial transcriptome of active human lung fibrogenesis sites with different human cell culture models to identify a disease-relevant model. Within the selected model, we then evaluate AB0023, identifying that it does not inhibit collagen cross-linking or reduce tissue stiffness, nor does it inhibit LOXL2 catalytic activity. In contrast, it does potently inhibit angiogenesis consistent with an alternative, non-enzymatic mechanism of action. Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffening. These findings have implications for the interpretation of the lack of efficacy of simtuzumab in clinical trials of fibrotic diseases.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035350","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}
Cell Reports MedicinePub Date : 2024-09-17Epub Date: 2024-08-28DOI: 10.1016/j.xcrm.2024.101700
Dennis S Metselaar, Michaël H Meel, Joshua R Goulding, Aimeé du Chatinier, Leyla Rigamonti, Piotr Waranecki, Neal Geisemeyer, Mark C de Gooijer, Marjolein Breur, Jan Koster, Sophie E M Veldhuijzen van Zanten, Marianna Bugiani, Niels E Franke, Alyssa Reddy, Pieter Wesseling, Gertjan J L Kaspers, Esther Hulleman
{"title":"Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.","authors":"Dennis S Metselaar, Michaël H Meel, Joshua R Goulding, Aimeé du Chatinier, Leyla Rigamonti, Piotr Waranecki, Neal Geisemeyer, Mark C de Gooijer, Marjolein Breur, Jan Koster, Sophie E M Veldhuijzen van Zanten, Marianna Bugiani, Niels E Franke, Alyssa Reddy, Pieter Wesseling, Gertjan J L Kaspers, Esther Hulleman","doi":"10.1016/j.xcrm.2024.101700","DOIUrl":"10.1016/j.xcrm.2024.101700","url":null,"abstract":"<p><p>Atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the sonic hedgehog (SHH) signaling activator GLI2, explaining the observed additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of ATRT xenograft-bearing mice with gemcitabine resulted in a >30% increase in median survival and yielded long-term survivors in two independent patient-derived xenograft models. These findings demonstrate that ATRTs are highly sensitive to gemcitabine treatment and may form part of a future multimodal treatment strategy for ATRTs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104785","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}
Yiran Zhang, John P. Thomas, Tamas Korcsmaros, Lejla Gul
{"title":"Integrating multi-omics to unravel host-microbiome interactions in inflammatory bowel disease","authors":"Yiran Zhang, John P. Thomas, Tamas Korcsmaros, Lejla Gul","doi":"10.1016/j.xcrm.2024.101738","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101738","url":null,"abstract":"<p>The gut microbiome is crucial for nutrient metabolism, immune regulation, and intestinal homeostasis with changes in its composition linked to complex diseases like inflammatory bowel disease (IBD). Although the precise host-microbial mechanisms in disease pathogenesis remain unclear, high-throughput sequencing have opened new ways to unravel the role of interspecies interactions in IBD. Systems biology—a holistic computational framework for modeling complex biological systems—is critical for leveraging multi-omics datasets to identify disease mechanisms. This review highlights the significance of multi-omics data in IBD research and provides an overview of state-of-the-art systems biology resources and computational tools for data integration. We explore gaps, challenges, and future directions in the research field aiming to uncover novel biomarkers and therapeutic targets, ultimately advancing personalized treatment strategies. While focusing on IBD, the proposed approaches are applicable for other complex diseases, like cancer, and neurodegenerative diseases, where the microbiome has also been implicated.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":14.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marta Nowak, Faiz Jabbar, Ann-Katrin Rodewald, Luciana Gneo, Tijana Tomasevic, Andrea Harkin, Tim Iveson, Mark Saunders, Rachel Kerr, Karin Oein, Noori Maka, Jennifer Hay, Joanne Edwards, Ian Tomlinson, Owen Sansom, Caroline Kelly, Francesco Pezzella, David Kerr, Alistair Easton, Enric Domingo, David N. Church
{"title":"Single-cell AI-based detection and prognostic and predictive value of DNA mismatch repair deficiency in colorectal cancer","authors":"Marta Nowak, Faiz Jabbar, Ann-Katrin Rodewald, Luciana Gneo, Tijana Tomasevic, Andrea Harkin, Tim Iveson, Mark Saunders, Rachel Kerr, Karin Oein, Noori Maka, Jennifer Hay, Joanne Edwards, Ian Tomlinson, Owen Sansom, Caroline Kelly, Francesco Pezzella, David Kerr, Alistair Easton, Enric Domingo, David N. Church","doi":"10.1016/j.xcrm.2024.101727","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101727","url":null,"abstract":"<p>Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (<em>P</em><sub>Interaction</sub> = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":14.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yang Yang, Tianduo Pei, Xiaolin Hu, Yu Lu, Yanqiu Huang, Tingya Wan, Chaobao Liu, Fengqian Chen, Bao Guo, Yuemei Hong, Qian Ba, Xiaoguang Li, Hui Wang
{"title":"Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell","authors":"Yang Yang, Tianduo Pei, Xiaolin Hu, Yu Lu, Yanqiu Huang, Tingya Wan, Chaobao Liu, Fengqian Chen, Bao Guo, Yuemei Hong, Qian Ba, Xiaoguang Li, Hui Wang","doi":"10.1016/j.xcrm.2024.101718","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101718","url":null,"abstract":"<p>The impact of dietary nutrients on tumor immunity remains an area of ongoing investigation, particularly regarding the specific role of vitamins and their mechanism. Here, we demonstrate that vitamin B3 (VB3) induces antitumor immunity against liver cancer through biased GPR109A axis in myeloid cell. Nutritional epidemiology studies suggest that higher VB3 intake reduces liver cancer risk. VB3 supplementation demonstrates antitumor efficacy in multiple mouse models through alleviating the immunosuppressive tumor microenvironment (TME) mediated by tumor-infiltrating myeloid cell, thereby augmenting effectiveness of immunotherapy or targeted therapy in a CD8<sup>+</sup> T cell-dependent manner. Mechanically, the TME induces aberrant GPR109A/nuclear factor κB (NF-κB) activation in myeloid cell to shape the immunosuppressive TME. In contrast, VB3 activates β-Arrestin-mediated GPR109A degradation and NF-κB inhibition to suppress the immunosuppressive polarization of myeloid cell, thereby activating the cytotoxic function of CD8<sup>+</sup> T cell. Overall, these results expand the understanding of how vitamins regulate the TME, suggesting that dietary VB3 supplementation is an adjunctive treatment for liver cancer.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":14.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting NAT10 inhibits osteosarcoma progression via ATF4/ASNS-mediated asparagine biosynthesis","authors":"Yutong Zou, Siyao Guo, Lili Wen, Dongming Lv, Jian Tu, Yan Liao, Weidong Chen, Ziyun Chen, Hongbo Li, Junkai Chen, Jingnan Shen, Xianbiao Xie","doi":"10.1016/j.xcrm.2024.101728","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101728","url":null,"abstract":"<p>Despite advances in treatment, the prognosis of patients with osteosarcoma remains unsatisfactory, and searching for potential targets is imperative. Here, we identify N4-acetylcytidine (ac4C) acetyltransferase 10 (NAT10) as a candidate therapeutic target in osteosarcoma through functional screening. NAT10 overexpression is correlated with a poor prognosis, and NAT10 knockout inhibits osteosarcoma progression. Mechanistically, NAT10 enhances mRNA stability of activating transcription factor 4 (ATF4) through ac4C modification. ATF4 induces the transcription of asparagine synthetase (ASNS), which catalyzes asparagine (Asn) biosynthesis, facilitating osteosarcoma progression. Utilizing virtual screening, we identify paliperidone and AG-401 as potential NAT10 inhibitors, and both inhibitors are found to bind to NAT10 proteins. Inhibiting NAT10 suppresses osteosarcoma progression <em>in vivo</em>. Combined treatment using paliperidone and AG-401 produces synergistic inhibition for osteosarcoma in patient-derived xenograft (PDX) models. Our findings demonstrate that NAT10 facilitates osteosarcoma progression through the ATF4/ASNS/Asn axis, and pharmacological inhibition of NAT10 may be a feasible therapeutic approach for osteosarcoma.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":14.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Phase 1a study of ESG401, a Trop2 antibody-drug conjugate, in patients with locally advanced/metastatic solid tumors.","authors":"Jiani Wang, Zhongsheng Tong, Yinuo Tan, Yehui Shi, Yun Wu, Qing Zhou, Xiaoyan Xing, Xiaomei Chen, Fuming Qiu, Fei Ma","doi":"10.1016/j.xcrm.2024.101707","DOIUrl":"10.1016/j.xcrm.2024.101707","url":null,"abstract":"<p><p>This phase 1a study assesses ESG401 in patients with heavily pretreated locally advanced or metastatic solid tumors, focusing on metastatic breast cancer. Forty patients are enrolled: three experience dose-limiting toxicities, establishing the maximum tolerated dose at 16 mg/kg on days 1, 8, and 15 of a 28-day cycle. The most common grade ≥3 treatment-related adverse events are neutropenia and leukopenia. Among 38 efficacy-evaluable patients, the objective response rate (ORR) is 34.2%, the disease control rate (DCR) is 65.8%, and the clinical benefit rate (CBR) is 50.0% (including stable disease for at least 6 months). The median progression-free survival is 5.1 months, and the median duration of response is 6.3 months. In patients receiving therapeutically relevant doses, the ORR, DCR, and CBR are 40.6%, 75.0%, and 56.3%, respectively. ESG401 demonstrates a favorable safety profile and promising antitumor activity in this heavily treated population. The trial is registered at ClinicalTrials.gov (NCT04892342).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104788","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}
{"title":"Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma.","authors":"Yaogang Zhong, Feng Geng, Logan Mazik, Xinmin Yin, Aline Paixao Becker, Shabber Mohammed, Huali Su, Enming Xing, Yongjun Kou, Cheng-Yao Chiang, Yunzhou Fan, Yongchen Guo, Qiang Wang, Pui-Kai Li, Xiaokui Mo, Etienne Lefai, Liqing He, Xiaolin Cheng, Xiang Zhang, Arnab Chakravarti, Deliang Guo","doi":"10.1016/j.xcrm.2024.101706","DOIUrl":"10.1016/j.xcrm.2024.101706","url":null,"abstract":"<p><p>Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis. These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo. Our findings underscore the promising therapeutic potential of effectively targeting GBM by combining glutamine metabolism inhibition with lysosome suppression.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139454","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}
Cell Reports MedicinePub Date : 2024-09-17Epub Date: 2024-08-28DOI: 10.1016/j.xcrm.2024.101699
Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy
{"title":"Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.","authors":"Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy","doi":"10.1016/j.xcrm.2024.101699","DOIUrl":"10.1016/j.xcrm.2024.101699","url":null,"abstract":"<p><p>Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104789","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}
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