Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01303-1
Aurpita Shaha, Yuanguo Wang, Xianghu Wang, Dong Wang, David Guinovart, Bin Liu, Ningling Kang
Liver metastasis of colorectal cancer (CRC) is a leading cause of death among cancer patients. The overexpression of glucose transporter 1 (Glut1) and enhanced glucose uptake that are associated with the Warburg effect are frequently observed in CRC liver metastases, but the underlying mechanisms remain poorly understood. CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) regulates the intracellular trafficking of programmed death-ligand-1 (PD-L1); therefore, we investigated whether CMTM6 regulates Glut1 trafficking and the Warburg effect in CRC cells. We found that knocking down of CMTM6 by shRNA induced the lysosomal degradation of Glut1, decreased glucose uptake and glycolysis in CRC cells, and suppressed subcutaneous CRC growth in nude mice and liver metastasis in C57BL/6 mice. Mechanistically, CMTM6 forms a complex with Glut1 and Rab11 in the endosomes of CRC cells, and this complex is required for the Rab11-dependent transport of Glut1 to the plasma membrane and for the protection of Glut1 from lysosomal degradation. Multiomics revealed global transcriptomic changes in CMTM6-knockdown CRC cells that affected the transcriptomes of adjacent cancer-associated fibroblasts from CRC liver metastases. As a result of these transcriptomic changes, CMTM6-knockdown CRC cells exhibited a defect in the G2-to-M phase transition, reduced secretion of 60 cytokines/chemokines, and inability to recruit cancer-associated fibroblasts to support an immunosuppressive CRC liver metastasis microenvironment. Analysis of TCGA data confirmed that CMTM6 expression was increased in CRC patients and that elevated CMTM6 expression was associated with worse patient survival. Together, our data suggest that CMTM6 plays multiple roles in regulating the Warburg effect, transcriptome, and liver metastasis of CRC. Liver metastasis in colorectal cancer patients increases death rates, with current treatments often inadequate due to a lack of understanding of the underlying processes. This study explores how CRC cells change their metabolism to survive in the liver, focusing on the Warburg effect, where cancer cells use glycolysis preferentially. It focuses on the role of a protein called CMTM6 in this metabolic change. The researchers performed experiments on human and mouse CRC cells and used both in vitro and in vivo models, including mice with and without immune systems, to study the effects of CMTM6 on CRC growth and liver metastasis. The results showed reducing CMTM6 levels led to decreased glycolysis of CRC cells, CRC tumor growth and liver metastasis in mice. Future studies could lead to more effective treatments for CRC patients with liver metastases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"CMTM6 mediates the Warburg effect and promotes the liver metastasis of colorectal cancer","authors":"Aurpita Shaha, Yuanguo Wang, Xianghu Wang, Dong Wang, David Guinovart, Bin Liu, Ningling Kang","doi":"10.1038/s12276-024-01303-1","DOIUrl":"10.1038/s12276-024-01303-1","url":null,"abstract":"Liver metastasis of colorectal cancer (CRC) is a leading cause of death among cancer patients. The overexpression of glucose transporter 1 (Glut1) and enhanced glucose uptake that are associated with the Warburg effect are frequently observed in CRC liver metastases, but the underlying mechanisms remain poorly understood. CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) regulates the intracellular trafficking of programmed death-ligand-1 (PD-L1); therefore, we investigated whether CMTM6 regulates Glut1 trafficking and the Warburg effect in CRC cells. We found that knocking down of CMTM6 by shRNA induced the lysosomal degradation of Glut1, decreased glucose uptake and glycolysis in CRC cells, and suppressed subcutaneous CRC growth in nude mice and liver metastasis in C57BL/6 mice. Mechanistically, CMTM6 forms a complex with Glut1 and Rab11 in the endosomes of CRC cells, and this complex is required for the Rab11-dependent transport of Glut1 to the plasma membrane and for the protection of Glut1 from lysosomal degradation. Multiomics revealed global transcriptomic changes in CMTM6-knockdown CRC cells that affected the transcriptomes of adjacent cancer-associated fibroblasts from CRC liver metastases. As a result of these transcriptomic changes, CMTM6-knockdown CRC cells exhibited a defect in the G2-to-M phase transition, reduced secretion of 60 cytokines/chemokines, and inability to recruit cancer-associated fibroblasts to support an immunosuppressive CRC liver metastasis microenvironment. Analysis of TCGA data confirmed that CMTM6 expression was increased in CRC patients and that elevated CMTM6 expression was associated with worse patient survival. Together, our data suggest that CMTM6 plays multiple roles in regulating the Warburg effect, transcriptome, and liver metastasis of CRC. Liver metastasis in colorectal cancer patients increases death rates, with current treatments often inadequate due to a lack of understanding of the underlying processes. This study explores how CRC cells change their metabolism to survive in the liver, focusing on the Warburg effect, where cancer cells use glycolysis preferentially. It focuses on the role of a protein called CMTM6 in this metabolic change. The researchers performed experiments on human and mouse CRC cells and used both in vitro and in vivo models, including mice with and without immune systems, to study the effects of CMTM6 on CRC growth and liver metastasis. The results showed reducing CMTM6 levels led to decreased glycolysis of CRC cells, CRC tumor growth and liver metastasis in mice. Future studies could lead to more effective treatments for CRC patients with liver metastases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 9","pages":"2002-2015"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01303-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114386","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 : 2024-09-02DOI: 10.1038/s12276-024-01299-8
Tae-Yong Choi, Sejin Jeong, Ja Wook Koo
Social animals, including rodents, primates, and humans, partake in competition for finite resources, thereby establishing social hierarchies wherein an individual’s social standing influences diverse behaviors. Understanding the neurobiological underpinnings of social dominance is imperative, given its ramifications for health, survival, and reproduction. Social dominance behavior comprises several facets, including social recognition, social decision-making, and actions, indicating the concerted involvement of multiple brain regions in orchestrating this behavior. While extensive research has been dedicated to elucidating the neurobiology of social interaction, recent studies have increasingly delved into adverse social behaviors such as social competition and hierarchy. This review focuses on the latest advancements in comprehending the mechanisms of the mesocorticolimbic circuit governing social dominance, with a specific focus on rodent studies, elucidating the intricate dynamics of social hierarchies and their implications for individual well-being and adaptation. In the animal world, the fight for food and mates often results in social rankings, with dominant animals getting better access to resources. This review explores the brain biology of social dominance, focusing on specific brain circuits in rodents. Using behavioral tests, they’ve started to understand how different brain areas and their connections affect social ranking among animals. The study combines results from many experiments to better understand how social dominance is wired in the brain. The results highlight the complexity of social dominance, showing it as a trait influenced by multiple brain areas and their interactions. They conclude that understanding these brain processes is key for understanding the wider implications of social behavior in health and disease. Their work improves our understanding of the biological basis of social hierarchies, suggesting potential targets for treating social behavior disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Mesocorticolimbic circuit mechanisms of social dominance behavior","authors":"Tae-Yong Choi, Sejin Jeong, Ja Wook Koo","doi":"10.1038/s12276-024-01299-8","DOIUrl":"10.1038/s12276-024-01299-8","url":null,"abstract":"Social animals, including rodents, primates, and humans, partake in competition for finite resources, thereby establishing social hierarchies wherein an individual’s social standing influences diverse behaviors. Understanding the neurobiological underpinnings of social dominance is imperative, given its ramifications for health, survival, and reproduction. Social dominance behavior comprises several facets, including social recognition, social decision-making, and actions, indicating the concerted involvement of multiple brain regions in orchestrating this behavior. While extensive research has been dedicated to elucidating the neurobiology of social interaction, recent studies have increasingly delved into adverse social behaviors such as social competition and hierarchy. This review focuses on the latest advancements in comprehending the mechanisms of the mesocorticolimbic circuit governing social dominance, with a specific focus on rodent studies, elucidating the intricate dynamics of social hierarchies and their implications for individual well-being and adaptation. In the animal world, the fight for food and mates often results in social rankings, with dominant animals getting better access to resources. This review explores the brain biology of social dominance, focusing on specific brain circuits in rodents. Using behavioral tests, they’ve started to understand how different brain areas and their connections affect social ranking among animals. The study combines results from many experiments to better understand how social dominance is wired in the brain. The results highlight the complexity of social dominance, showing it as a trait influenced by multiple brain areas and their interactions. They conclude that understanding these brain processes is key for understanding the wider implications of social behavior in health and disease. Their work improves our understanding of the biological basis of social hierarchies, suggesting potential targets for treating social behavior disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 9","pages":"1889-1899"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01299-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114390","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}
Agonists targeting α2-adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, attention-deficit/hyperactivity disorder, pain, panic disorders, opioid and alcohol withdrawal symptoms, and cigarette cravings. These receptors transduce signals through heterotrimeric Gi proteins. Here, we elucidated cryo-EM structures that depict α2A-AR in complex with Gi proteins, along with the endogenous agonist epinephrine or the synthetic agonist dexmedetomidine. Molecular dynamics simulations and functional studies reinforce the results of the structural revelations. Our investigation revealed that epinephrine exhibits different conformations when engaging with α-ARs and β-ARs. Furthermore, α2A-AR and β1-AR (primarily coupled to Gs, with secondary associations to Gi) were compared and found to exhibit different interactions with Gi proteins. Notably, the stability of the epinephrine–α2A-AR–Gi complex is greater than that of the dexmedetomidine–α2A-AR–Gi complex. These findings substantiate and improve our knowledge on the intricate signaling mechanisms orchestrated by ARs and concurrently shed light on the regulation of α-ARs and β-ARs by epinephrine. Our bodies have a system, the sympathetic nervous system, that uses certain chemicals to control heart rate, blood pressure, etc. These chemicals, epinephrine and norepinephrine, work by activating proteins known as adrenergic receptors. Understanding these receptors could help treat diseases like high blood pressure and ADHD. This study used a method called cryo-electron microscopy to see how epinephrine interacts with these receptors. It compared how epinephrine and a similar drug, dexmedetomidine, interact with the receptors. The study found that epinephrine binds to the α and β types of the receptors differently, which could explain their different effects. This helps us understand how drugs that mimic or block epinephrine can treat diseases. This could lead to new, more effective drugs. Future research may use these findings to design better treatments for heart diseases and other conditions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
以α2肾上腺素能受体（ARs）为靶点的激动剂可用于治疗多种疾病，包括高血压、注意力缺陷/多动障碍、疼痛、恐慌症、阿片类药物和酒精戒断症状以及烟瘾。这些受体通过异三聚 Gi 蛋白传递信号。在这里，我们阐明了描述α2A-AR与Gi蛋白以及内源性激动剂肾上腺素或合成激动剂右美托咪定复合物的低温电子显微镜结构。分子动力学模拟和功能研究加强了结构揭示的结果。我们的研究发现，肾上腺素在与α-ARs 和 β-ARs 结合时呈现出不同的构象。此外，我们还比较了α2A-AR 和 β1-AR（主要与 Gs 耦合，次要与 Gi 关联），发现它们与 Gi 蛋白的相互作用各不相同。值得注意的是，肾上腺素-α2A-AR-Gi 复合物的稳定性高于右美托咪定-α2A-AR-Gi 复合物。这些发现证实并提高了我们对 ARs 错综复杂的信号转导机制的认识，同时也揭示了肾上腺素对 α-ARs 和 β-ARs 的调控作用。
{"title":"Distinct binding conformations of epinephrine with α- and β-adrenergic receptors","authors":"Jian-Shu Lou, Minfei Su, Jinan Wang, Hung Nguyen Do, Yinglong Miao, Xin-Yun Huang","doi":"10.1038/s12276-024-01296-x","DOIUrl":"10.1038/s12276-024-01296-x","url":null,"abstract":"Agonists targeting α2-adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, attention-deficit/hyperactivity disorder, pain, panic disorders, opioid and alcohol withdrawal symptoms, and cigarette cravings. These receptors transduce signals through heterotrimeric Gi proteins. Here, we elucidated cryo-EM structures that depict α2A-AR in complex with Gi proteins, along with the endogenous agonist epinephrine or the synthetic agonist dexmedetomidine. Molecular dynamics simulations and functional studies reinforce the results of the structural revelations. Our investigation revealed that epinephrine exhibits different conformations when engaging with α-ARs and β-ARs. Furthermore, α2A-AR and β1-AR (primarily coupled to Gs, with secondary associations to Gi) were compared and found to exhibit different interactions with Gi proteins. Notably, the stability of the epinephrine–α2A-AR–Gi complex is greater than that of the dexmedetomidine–α2A-AR–Gi complex. These findings substantiate and improve our knowledge on the intricate signaling mechanisms orchestrated by ARs and concurrently shed light on the regulation of α-ARs and β-ARs by epinephrine. Our bodies have a system, the sympathetic nervous system, that uses certain chemicals to control heart rate, blood pressure, etc. These chemicals, epinephrine and norepinephrine, work by activating proteins known as adrenergic receptors. Understanding these receptors could help treat diseases like high blood pressure and ADHD. This study used a method called cryo-electron microscopy to see how epinephrine interacts with these receptors. It compared how epinephrine and a similar drug, dexmedetomidine, interact with the receptors. The study found that epinephrine binds to the α and β types of the receptors differently, which could explain their different effects. This helps us understand how drugs that mimic or block epinephrine can treat diseases. This could lead to new, more effective drugs. Future research may use these findings to design better treatments for heart diseases and other conditions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 9","pages":"1952-1966"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01296-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114387","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 : 2024-08-29DOI: 10.1038/s12276-024-01309-9
Luping Du, Xuyang Wang, Yan Guo, Tingting Tao, Hong Wu, Xiaodong Xu, Bohuan Zhang, Ting Chen, Qingbo Xu, Xiaogang Guo
Hyperlipidemia and hypertension might play a role in cardiac fibrosis, in which a heterogeneous population of fibroblasts seems important. However, it is unknown whether CD34+ progenitor cells are involved in the pathogenesis of heart fibrosis. This study aimed to explore the mechanism of CD34+ cell differentiation in cardiac fibrosis during hyperlipidemia. Through the analysis of transcriptomes from 50,870 single cells extracted from mouse hearts and 76,851 single cells from human hearts, we have effectively demonstrated the evolving cellular landscape throughout cardiac fibrosis. Disturbances in lipid metabolism can accelerate the development of fibrosis. Through the integration of bone marrow transplantation models and lineage tracing, our study showed that hyperlipidemia can expedite the differentiation of non-bone marrow-derived CD34+ cells into fibroblasts, particularly FABP4+ fibroblasts, in response to angiotensin II. Interestingly, the partial depletion of CD34+ cells led to a notable reduction in triglycerides in the heart, mitigated fibrosis, and improved cardiac function. Furthermore, immunostaining of human heart tissue revealed colocalization of CD34+ cells and fibroblasts. Mechanistically, our investigation of single-cell RNA sequencing data through pseudotime analysis combined with in vitro cellular studies revealed the crucial role of the PPARγ/Akt/Gsk3β pathway in orchestrating the differentiation of CD34+ cells into FABP4+ fibroblasts. Through our study, we generated valuable insights into the cellular landscape of CD34+ cell-derived cells in the hypertrophic heart with hyperlipidemia, indicating that the differentiation of non-bone marrow-derived CD34+ cells into FABP4+ fibroblasts during this process accelerates lipid accumulation and promotes heart failure via the PPARγ/Akt/Gsk3β pathway. Cardiac fibrosis, a condition leading to heart failure, is caused by the activation of cardiac fibroblasts. These cells are influenced by various factors, including disorders in lipid metabolism. The role of lipid metabolism in cardiac fibrosis, particularly under conditions like hyperlipidemia and hypertension, is not fully understood. This study investigates how lipid metabolism disorders affect cardiac fibrosis and the role of certain cells in this process. The research uses human heart samples and mouse models, including a specific type of genetically modified mouse with induced hypertension. The study reveals that lipid metabolism disorders significantly contribute to cardiac fibrosis by promoting the transformation of CD34+ cells into FABP4+ fibroblasts, worsening heart fibrosis. The findings suggest potential new treatments for cardiac fibrosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Altered lipid metabolism promoting cardiac fibrosis is mediated by CD34+ cell-derived FABP4+ fibroblasts","authors":"Luping Du, Xuyang Wang, Yan Guo, Tingting Tao, Hong Wu, Xiaodong Xu, Bohuan Zhang, Ting Chen, Qingbo Xu, Xiaogang Guo","doi":"10.1038/s12276-024-01309-9","DOIUrl":"10.1038/s12276-024-01309-9","url":null,"abstract":"Hyperlipidemia and hypertension might play a role in cardiac fibrosis, in which a heterogeneous population of fibroblasts seems important. However, it is unknown whether CD34+ progenitor cells are involved in the pathogenesis of heart fibrosis. This study aimed to explore the mechanism of CD34+ cell differentiation in cardiac fibrosis during hyperlipidemia. Through the analysis of transcriptomes from 50,870 single cells extracted from mouse hearts and 76,851 single cells from human hearts, we have effectively demonstrated the evolving cellular landscape throughout cardiac fibrosis. Disturbances in lipid metabolism can accelerate the development of fibrosis. Through the integration of bone marrow transplantation models and lineage tracing, our study showed that hyperlipidemia can expedite the differentiation of non-bone marrow-derived CD34+ cells into fibroblasts, particularly FABP4+ fibroblasts, in response to angiotensin II. Interestingly, the partial depletion of CD34+ cells led to a notable reduction in triglycerides in the heart, mitigated fibrosis, and improved cardiac function. Furthermore, immunostaining of human heart tissue revealed colocalization of CD34+ cells and fibroblasts. Mechanistically, our investigation of single-cell RNA sequencing data through pseudotime analysis combined with in vitro cellular studies revealed the crucial role of the PPARγ/Akt/Gsk3β pathway in orchestrating the differentiation of CD34+ cells into FABP4+ fibroblasts. Through our study, we generated valuable insights into the cellular landscape of CD34+ cell-derived cells in the hypertrophic heart with hyperlipidemia, indicating that the differentiation of non-bone marrow-derived CD34+ cells into FABP4+ fibroblasts during this process accelerates lipid accumulation and promotes heart failure via the PPARγ/Akt/Gsk3β pathway. Cardiac fibrosis, a condition leading to heart failure, is caused by the activation of cardiac fibroblasts. These cells are influenced by various factors, including disorders in lipid metabolism. The role of lipid metabolism in cardiac fibrosis, particularly under conditions like hyperlipidemia and hypertension, is not fully understood. This study investigates how lipid metabolism disorders affect cardiac fibrosis and the role of certain cells in this process. The research uses human heart samples and mouse models, including a specific type of genetically modified mouse with induced hypertension. The study reveals that lipid metabolism disorders significantly contribute to cardiac fibrosis by promoting the transformation of CD34+ cells into FABP4+ fibroblasts, worsening heart fibrosis. The findings suggest potential new treatments for cardiac fibrosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 8","pages":"1869-1886"},"PeriodicalIF":9.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01309-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094130","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 : 2024-08-13DOI: 10.1038/s12276-024-01288-x
Ryul Kim, Seokhwi Kim, Brian Baek-Lok Oh, Woo Sik Yu, Chang Woo Kim, Hoon Hur, Sang-Yong Son, Min Jae Yang, Dae Sung Cho, Taeyang Ha, Subin Heo, Jeon Yeob Jang, Jae Sung Yun, Kyu-Sung Kwack, Jai Keun Kim, Jimi Huh, Sun Gyo Lim, Sang-Uk Han, Hyun Woo Lee, Ji Eun Park, Chul-Ho Kim, Jin Roh, Young Wha Koh, Dakeun Lee, Jang-Hee Kim, Gil Ho Lee, Choong-Kyun Noh, Yun Jung Jung, Ji Won Park, Seungsoo Sheen, Mi Sun Ahn, Yong Won Choi, Tae-Hwan Kim, Seok Yun Kang, Jin-Hyuk Choi, Soo Yeon Baek, Kee Myung Lee, Sun Il Kim, Sung Hyun Noh, Se-Hyuk Kim, Hyemin Hwang, Eunjung Joo, Shinjung Lee, Jong-Yeon Shin, Ji-Young Yun, Junggil Park, Kijong Yi, Youngoh Kwon, Won-Chul Lee, Hansol Park, Joonoh Lim, Boram Yi, Jaemo Koo, June-Young Koh, Sangmoon Lee, Yuna Lee, Bo-Rahm Lee, Erin Connolly-Strong, Young Seok Ju, Minsuk Kwon
Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management. Personalized medicine customizes cancer treatment to each patient, using molecular profiling of tumors to find specific genetic changes that can guide treatment. Despite progress, the practical use of whole-genome sequencing in clinical settings is still not fully explored. This study examines the use of WGS for cancer patients, aiming to make it a regular part of care. The study involved 120 participants with various solid tumors, using the CancerVisionTM for sequencing. Researchers conclude that WGS is a valuable tool in precision oncology, offering insights that can significantly impact treatment strategies. The study marks progress in integration of genomic medicine into clinical practice, showcasing the feasibility and benefits of WGS in a real-world hospital setting. Future research may further establish WGS as a standard part of cancer care, potentially changing how we approach treatment for different tumor types. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Clinical application of whole-genome sequencing of solid tumors for precision oncology","authors":"Ryul Kim, Seokhwi Kim, Brian Baek-Lok Oh, Woo Sik Yu, Chang Woo Kim, Hoon Hur, Sang-Yong Son, Min Jae Yang, Dae Sung Cho, Taeyang Ha, Subin Heo, Jeon Yeob Jang, Jae Sung Yun, Kyu-Sung Kwack, Jai Keun Kim, Jimi Huh, Sun Gyo Lim, Sang-Uk Han, Hyun Woo Lee, Ji Eun Park, Chul-Ho Kim, Jin Roh, Young Wha Koh, Dakeun Lee, Jang-Hee Kim, Gil Ho Lee, Choong-Kyun Noh, Yun Jung Jung, Ji Won Park, Seungsoo Sheen, Mi Sun Ahn, Yong Won Choi, Tae-Hwan Kim, Seok Yun Kang, Jin-Hyuk Choi, Soo Yeon Baek, Kee Myung Lee, Sun Il Kim, Sung Hyun Noh, Se-Hyuk Kim, Hyemin Hwang, Eunjung Joo, Shinjung Lee, Jong-Yeon Shin, Ji-Young Yun, Junggil Park, Kijong Yi, Youngoh Kwon, Won-Chul Lee, Hansol Park, Joonoh Lim, Boram Yi, Jaemo Koo, June-Young Koh, Sangmoon Lee, Yuna Lee, Bo-Rahm Lee, Erin Connolly-Strong, Young Seok Ju, Minsuk Kwon","doi":"10.1038/s12276-024-01288-x","DOIUrl":"10.1038/s12276-024-01288-x","url":null,"abstract":"Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management. Personalized medicine customizes cancer treatment to each patient, using molecular profiling of tumors to find specific genetic changes that can guide treatment. Despite progress, the practical use of whole-genome sequencing in clinical settings is still not fully explored. This study examines the use of WGS for cancer patients, aiming to make it a regular part of care. The study involved 120 participants with various solid tumors, using the CancerVisionTM for sequencing. Researchers conclude that WGS is a valuable tool in precision oncology, offering insights that can significantly impact treatment strategies. The study marks progress in integration of genomic medicine into clinical practice, showcasing the feasibility and benefits of WGS in a real-world hospital setting. Future research may further establish WGS as a standard part of cancer care, potentially changing how we approach treatment for different tumor types. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 8","pages":"1856-1868"},"PeriodicalIF":9.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01288-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977070","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 : 2024-08-09DOI: 10.1038/s12276-024-01280-5
Dongwei Xu, Xiaoye Qu, Tao Yang, Mingwei Sheng, Xiyun Bian, Yongqiang Zhan, Yizhu Tian, Yuanbang Lin, Yuting Jin, Xiao Wang, Michael Ke, Longfeng Jiang, Changyong Li, Qiang Xia, Douglas G. Farmer, Bibo Ke
Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1–YAP–Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH. In the battle against nonalcoholic steatohepatitis, it’s vital to understand how our immune system contributes to liver harm. Researchers found that a protein named STING is crucial in liver inflammation and damage as it identifies damaged DNA. They investigate how certain proteins and processes in immune cells affect STING’s function and NASH’s progression. Researchers discovered that decreasing the activity of a protein named Foxo1 in macrophagesresults in less liver damage and inflammation in mice on a high-fat diet. They also examined how other signaling processes, like the Hippo–YAP and Notch1 processes, interact with STING and contribute to the disease. Their findings indicate that adjusting these processes can reduce liver damage, steatosis, and inflammation, suggesting new potential treatment targets for NASH, potentially improving the lives of those affected by this condition.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The Foxo1-YAP-Notch1 axis reprograms STING-mediated innate immunity in NASH progression","authors":"Dongwei Xu, Xiaoye Qu, Tao Yang, Mingwei Sheng, Xiyun Bian, Yongqiang Zhan, Yizhu Tian, Yuanbang Lin, Yuting Jin, Xiao Wang, Michael Ke, Longfeng Jiang, Changyong Li, Qiang Xia, Douglas G. Farmer, Bibo Ke","doi":"10.1038/s12276-024-01280-5","DOIUrl":"10.1038/s12276-024-01280-5","url":null,"abstract":"Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1–YAP–Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH. In the battle against nonalcoholic steatohepatitis, it’s vital to understand how our immune system contributes to liver harm. Researchers found that a protein named STING is crucial in liver inflammation and damage as it identifies damaged DNA. They investigate how certain proteins and processes in immune cells affect STING’s function and NASH’s progression. Researchers discovered that decreasing the activity of a protein named Foxo1 in macrophagesresults in less liver damage and inflammation in mice on a high-fat diet. They also examined how other signaling processes, like the Hippo–YAP and Notch1 processes, interact with STING and contribute to the disease. Their findings indicate that adjusting these processes can reduce liver damage, steatosis, and inflammation, suggesting new potential treatment targets for NASH, potentially improving the lives of those affected by this condition.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 8","pages":"1843-1855"},"PeriodicalIF":9.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01280-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914428","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}
Abnormal cardiac development has been observed in individuals with Cornelia de Lange syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. However, the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed that CdLS patients with SMC3 mutations have high rates of congenital heart disease (CHD). We utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which exhibit varying degrees of outflow tract (OFT) abnormalities, to further explore this relationship. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. By employing single-nucleus RNA sequencing and chromosome conformation capture high-throughput genome-wide translocation sequencing, we revealed that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SEs) and promoters. Notably, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research revealed a novel role for SMC3 in heart development via the regulation of SE-associated genes, suggesting its potential relevance as a CHD-related gene and providing crucial insights into the molecular basis of cardiac development. Understanding heart development is vital as defects in this process are a major cause of birth abnormalities. This study focuses on a protein, SMC3, and its role in heart development. Experiments were conducted on mice genetically altered to lack SMC3 in heart cells. Researchers found that mice without SMC3 had various heart defects, like those seen in humans with congenital heart disease. They also found mutations in the SMC3 gene in patients with congenital heart disease, suggesting a link between SMC3 and heart development in humans. The findings reveal that SMC3 plays a crucial role in heart development, with its absence leading to significant heart defects in mice. These results suggest a potential genetic cause for some forms of congenital heart disease in humans. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. Introduction
{"title":"SMC3 contributes to heart development by regulating super-enhancer associated genes","authors":"Bowen Zhang, Yongchang Zhu, Zhen Zhang, Feizhen Wu, Xiaojing Ma, Wei Sheng, Ranran Dai, Zhenglong Guo, Weili Yan, Lili Hao, Guoying Huang, Duan Ma, Bingtao Hao, Jing Ma","doi":"10.1038/s12276-024-01293-0","DOIUrl":"10.1038/s12276-024-01293-0","url":null,"abstract":"Abnormal cardiac development has been observed in individuals with Cornelia de Lange syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. However, the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed that CdLS patients with SMC3 mutations have high rates of congenital heart disease (CHD). We utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which exhibit varying degrees of outflow tract (OFT) abnormalities, to further explore this relationship. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. By employing single-nucleus RNA sequencing and chromosome conformation capture high-throughput genome-wide translocation sequencing, we revealed that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SEs) and promoters. Notably, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research revealed a novel role for SMC3 in heart development via the regulation of SE-associated genes, suggesting its potential relevance as a CHD-related gene and providing crucial insights into the molecular basis of cardiac development. Understanding heart development is vital as defects in this process are a major cause of birth abnormalities. This study focuses on a protein, SMC3, and its role in heart development. Experiments were conducted on mice genetically altered to lack SMC3 in heart cells. Researchers found that mice without SMC3 had various heart defects, like those seen in humans with congenital heart disease. They also found mutations in the SMC3 gene in patients with congenital heart disease, suggesting a link between SMC3 and heart development in humans. The findings reveal that SMC3 plays a crucial role in heart development, with its absence leading to significant heart defects in mice. These results suggest a potential genetic cause for some forms of congenital heart disease in humans. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. Introduction","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 8","pages":"1826-1842"},"PeriodicalIF":9.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01293-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861489","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 : 2024-08-01DOI: 10.1038/s12276-024-01286-z
Yeon Jun Kang, Woorim Song, Su Jeong Lee, Seung Ah Choi, Sihyun Chae, Bo Ruem Yoon, Hee Young Kim, Jung Ho Lee, Chulwoo Kim, Joo-Youn Cho, Hyun Je Kim, Won-Woo Lee
Branched-chain amino acids (BCAAs), particularly leucine, are indispensable AAs for immune regulation through metabolic rewiring. However, the molecular mechanism underlying this phenomenon remains unclear. Our investigation revealed that T-cell receptor (TCR)-activated human CD4+ T cells increase the expression of BCAT1, a cytosolic enzyme responsible for BCAA catabolism, and SLC7A5, a major BCAA transporter. This upregulation facilitates increased leucine influx and catabolism, which are particularly crucial for Th17 responses. Activated CD4+ T cells induce an alternative pathway of cytosolic leucine catabolism, generating a pivotal metabolite, β-hydroxy β-methylbutyric acid (HMB), by acting on BCAT1 and 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HPDL). Inhibition of BCAT1-mediated cytosolic leucine metabolism, either with BCAT1 inhibitor 2 (Bi2) or through BCAT1, HPD, or HPDL silencing using shRNA, attenuates IL-17 production, whereas HMB supplementation abrogates this effect. Mechanistically, HMB contributes to the regulation of the mTORC1-HIF1α pathway, a major signaling pathway for IL-17 production, by increasing the mRNA expression of HIF1α. This finding was corroborated by the observation that treatment with L-β-homoleucine (LβhL), a leucine analog and competitive inhibitor of BCAT1, decreased IL-17 production by TCR-activated CD4+ T cells. In an in vivo experimental autoimmune encephalomyelitis (EAE) model, blockade of BCAT1-mediated leucine catabolism, either through a BCAT1 inhibitor or LβhL treatment, mitigated EAE severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells. Our findings elucidate the role of BCAT1-mediated cytoplasmic leucine catabolism in modulating IL-17 production via HMB-mediated regulation of mTORC1-HIF1α, providing insights into its relevance to inflammatory conditions. T-cell, a type of infection-fighting white blood cell, alter their metabolic process, relying heavily on amino acids, the building blocks of proteins. This study investigates how T cells use the amino acid leucine to power their response. Researchers conducted experiments with human T-cell and a mouse model of autoimmune disease, a condition where the body attacks its own cells. They studied how leucine’s metabolic process affects T-cell function. The study discovered that a specific process involving leucine’s metabolic pathway in T cells is vital for their ability to produce IL-17. Blocking a crucial enzyme reduced IL-17 production and eased symptoms in a mouse model of autoimmune disease. These findings underline the importance of leucine’s metabolic process in T-cell function and suggest a potential target for treating autoimmune diseases more effectively, offering hope for new treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Inhibition of BCAT1-mediated cytosolic leucine metabolism regulates Th17 responses via the mTORC1-HIF1α pathway","authors":"Yeon Jun Kang, Woorim Song, Su Jeong Lee, Seung Ah Choi, Sihyun Chae, Bo Ruem Yoon, Hee Young Kim, Jung Ho Lee, Chulwoo Kim, Joo-Youn Cho, Hyun Je Kim, Won-Woo Lee","doi":"10.1038/s12276-024-01286-z","DOIUrl":"10.1038/s12276-024-01286-z","url":null,"abstract":"Branched-chain amino acids (BCAAs), particularly leucine, are indispensable AAs for immune regulation through metabolic rewiring. However, the molecular mechanism underlying this phenomenon remains unclear. Our investigation revealed that T-cell receptor (TCR)-activated human CD4+ T cells increase the expression of BCAT1, a cytosolic enzyme responsible for BCAA catabolism, and SLC7A5, a major BCAA transporter. This upregulation facilitates increased leucine influx and catabolism, which are particularly crucial for Th17 responses. Activated CD4+ T cells induce an alternative pathway of cytosolic leucine catabolism, generating a pivotal metabolite, β-hydroxy β-methylbutyric acid (HMB), by acting on BCAT1 and 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HPDL). Inhibition of BCAT1-mediated cytosolic leucine metabolism, either with BCAT1 inhibitor 2 (Bi2) or through BCAT1, HPD, or HPDL silencing using shRNA, attenuates IL-17 production, whereas HMB supplementation abrogates this effect. Mechanistically, HMB contributes to the regulation of the mTORC1-HIF1α pathway, a major signaling pathway for IL-17 production, by increasing the mRNA expression of HIF1α. This finding was corroborated by the observation that treatment with L-β-homoleucine (LβhL), a leucine analog and competitive inhibitor of BCAT1, decreased IL-17 production by TCR-activated CD4+ T cells. In an in vivo experimental autoimmune encephalomyelitis (EAE) model, blockade of BCAT1-mediated leucine catabolism, either through a BCAT1 inhibitor or LβhL treatment, mitigated EAE severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells. Our findings elucidate the role of BCAT1-mediated cytoplasmic leucine catabolism in modulating IL-17 production via HMB-mediated regulation of mTORC1-HIF1α, providing insights into its relevance to inflammatory conditions. T-cell, a type of infection-fighting white blood cell, alter their metabolic process, relying heavily on amino acids, the building blocks of proteins. This study investigates how T cells use the amino acid leucine to power their response. Researchers conducted experiments with human T-cell and a mouse model of autoimmune disease, a condition where the body attacks its own cells. They studied how leucine’s metabolic process affects T-cell function. The study discovered that a specific process involving leucine’s metabolic pathway in T cells is vital for their ability to produce IL-17. Blocking a crucial enzyme reduced IL-17 production and eased symptoms in a mouse model of autoimmune disease. These findings underline the importance of leucine’s metabolic process in T-cell function and suggest a potential target for treating autoimmune diseases more effectively, offering hope for new treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 8","pages":"1776-1790"},"PeriodicalIF":9.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01286-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861486","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 : 2024-08-01DOI: 10.1038/s12276-024-01291-2
Cho-Rong Lee, Jungyo Suh, Dongjun Jang, Bo-Yeong Jin, Jaeso Cho, Moses Lee, Hyungtai Sim, Minyong Kang, Jueun Lee, Ju Hyun Park, Kyoung-Hwa Lee, Geum-Sook Hwang, Kyung Chul Moon, Cheryn Song, Ja Hyeon Ku, Cheol Kwak, Hyeon Hoe Kim, Sung-Yup Cho, Murim Choi, Chang Wook Jeong
TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC. Understanding the unique traits of a rare kidney cancer type, TFE3-rearranged renal cell carcinoma, is important due to its poor response to usual treatments. This study explores the genetic and metabolic makeup of tRCC, comparing it with clear cell RCC and normal kidney cells. Using a mix of cell culture, whole exome sequencing, and various molecular analyses, the team conducted an experiment to reveal the unique genetic and metabolic profiles of tRCC. The researchers conclude that targeting the metabolic changes in tRCC, specifically through inhibiting PPARGC1A-mediated mitochondrial respiration, offers a new treatment approach. This approach marks a significant step in understanding and potentially treating tRCC. The implications of this study could lead to more effective treatments for patients with this challenging cancer type, emphasizing the importance of metabolic pathways in cancer therapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma","authors":"Cho-Rong Lee, Jungyo Suh, Dongjun Jang, Bo-Yeong Jin, Jaeso Cho, Moses Lee, Hyungtai Sim, Minyong Kang, Jueun Lee, Ju Hyun Park, Kyoung-Hwa Lee, Geum-Sook Hwang, Kyung Chul Moon, Cheryn Song, Ja Hyeon Ku, Cheol Kwak, Hyeon Hoe Kim, Sung-Yup Cho, Murim Choi, Chang Wook Jeong","doi":"10.1038/s12276-024-01291-2","DOIUrl":"10.1038/s12276-024-01291-2","url":null,"abstract":"TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC. Understanding the unique traits of a rare kidney cancer type, TFE3-rearranged renal cell carcinoma, is important due to its poor response to usual treatments. This study explores the genetic and metabolic makeup of tRCC, comparing it with clear cell RCC and normal kidney cells. Using a mix of cell culture, whole exome sequencing, and various molecular analyses, the team conducted an experiment to reveal the unique genetic and metabolic profiles of tRCC. The researchers conclude that targeting the metabolic changes in tRCC, specifically through inhibiting PPARGC1A-mediated mitochondrial respiration, offers a new treatment approach. This approach marks a significant step in understanding and potentially treating tRCC. The implications of this study could lead to more effective treatments for patients with this challenging cancer type, emphasizing the importance of metabolic pathways in cancer therapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 8","pages":"1807-1815"},"PeriodicalIF":9.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01291-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861485","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}
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