Pub Date : 2024-06-20DOI: 10.1038/s41556-024-01442-7
Katarina Harasimov, Rebecca L. Gorry, Luisa M. Welp, Sarah Mae Penir, Yehor Horokhovskyi, Shiya Cheng, Katsuyoshi Takaoka, Alexandra Stützer, Ann-Sophie Frombach, Ana Lisa Taylor Tavares, Monika Raabe, Sara Haag, Debojit Saha, Katharina Grewe, Vera Schipper, Silvio O. Rizzoli, Henning Urlaub, Juliane Liepe, Melina Schuh
Women are born with all of their oocytes. The oocyte proteome must be maintained with minimal damage throughout the woman’s reproductive life, and hence for decades. Here we report that oocyte and ovarian proteostasis involves extreme protein longevity. Mouse ovaries had more extremely long-lived proteins than other tissues, including brain. These long-lived proteins had diverse functions, including in mitochondria, the cytoskeleton, chromatin and proteostasis. The stable proteins resided not only in oocytes but also in long-lived ovarian somatic cells. Our data suggest that mammals increase protein longevity and enhance proteostasis by chaperones and cellular antioxidants to maintain the female germline for long periods. Indeed, protein aggregation in oocytes did not increase with age and proteasome activity did not decay. However, increasing protein longevity cannot fully block female germline senescence. Large-scale proteome profiling of ~8,890 proteins revealed a decline in many long-lived proteins of the proteostasis network in the aging ovary, accompanied by massive proteome remodeling, which eventually leads to female fertility decline. Harasimov, Gorry, Welp, Penir, Horokhovskyi et al. analyse proteostasis in mammalian oocytes and ovaries: the maintenance of oocytes involves exceptional protein longevity, and many of the extremely long-lived proteins decline as the ovary ages.
{"title":"The maintenance of oocytes in the mammalian ovary involves extreme protein longevity","authors":"Katarina Harasimov, Rebecca L. Gorry, Luisa M. Welp, Sarah Mae Penir, Yehor Horokhovskyi, Shiya Cheng, Katsuyoshi Takaoka, Alexandra Stützer, Ann-Sophie Frombach, Ana Lisa Taylor Tavares, Monika Raabe, Sara Haag, Debojit Saha, Katharina Grewe, Vera Schipper, Silvio O. Rizzoli, Henning Urlaub, Juliane Liepe, Melina Schuh","doi":"10.1038/s41556-024-01442-7","DOIUrl":"10.1038/s41556-024-01442-7","url":null,"abstract":"Women are born with all of their oocytes. The oocyte proteome must be maintained with minimal damage throughout the woman’s reproductive life, and hence for decades. Here we report that oocyte and ovarian proteostasis involves extreme protein longevity. Mouse ovaries had more extremely long-lived proteins than other tissues, including brain. These long-lived proteins had diverse functions, including in mitochondria, the cytoskeleton, chromatin and proteostasis. The stable proteins resided not only in oocytes but also in long-lived ovarian somatic cells. Our data suggest that mammals increase protein longevity and enhance proteostasis by chaperones and cellular antioxidants to maintain the female germline for long periods. Indeed, protein aggregation in oocytes did not increase with age and proteasome activity did not decay. However, increasing protein longevity cannot fully block female germline senescence. Large-scale proteome profiling of ~8,890 proteins revealed a decline in many long-lived proteins of the proteostasis network in the aging ovary, accompanied by massive proteome remodeling, which eventually leads to female fertility decline. Harasimov, Gorry, Welp, Penir, Horokhovskyi et al. analyse proteostasis in mammalian oocytes and ovaries: the maintenance of oocytes involves exceptional protein longevity, and many of the extremely long-lived proteins decline as the ovary ages.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01442-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-17DOI: 10.1038/s41556-024-01432-9
Roberta Palmulli, Mickaël Couty, Melissa C. Piontek, Maharajah Ponnaiah, Florent Dingli, Frederik J. Verweij, Stéphanie Charrin, Matteo Tantucci, Sajitha Sasidharan, Eric Rubinstein, Anatol Kontush, Damarys Loew, Marie Lhomme, Wouter H. Roos, Graça Raposo, Guillaume van Niel
Extracellular vesicles such as exosomes are now recognized as key players in intercellular communication. Their role is influenced by the specific repertoires of proteins and lipids, which are enriched when they are generated as intraluminal vesicles (ILVs) in multivesicular endosomes. Here we report that a key component of small extracellular vesicles, the tetraspanin CD63, sorts cholesterol to ILVs, generating a pool that can be mobilized by the NPC1/2 complex, and exported via exosomes to recipient cells. In the absence of CD63, cholesterol is retrieved from the endosomes by actin-dependent vesicular transport, placing CD63 and cholesterol at the centre of a balance between inward and outward budding of endomembranes. These results establish CD63 as a lipid-sorting mechanism within endosomes, and show that ILVs and exosomes are alternative providers of cholesterol. Palmulli, Couty and colleagues show that the tetraspanin CD63 promotes accumulation of cholesterol in intraluminal vesicles (ILVs) at the expense of retrieval from endosomes; cholesterol stored in ILVs and exosomes is recovered in an NPC1-dependent manner.
{"title":"CD63 sorts cholesterol into endosomes for storage and distribution via exosomes","authors":"Roberta Palmulli, Mickaël Couty, Melissa C. Piontek, Maharajah Ponnaiah, Florent Dingli, Frederik J. Verweij, Stéphanie Charrin, Matteo Tantucci, Sajitha Sasidharan, Eric Rubinstein, Anatol Kontush, Damarys Loew, Marie Lhomme, Wouter H. Roos, Graça Raposo, Guillaume van Niel","doi":"10.1038/s41556-024-01432-9","DOIUrl":"10.1038/s41556-024-01432-9","url":null,"abstract":"Extracellular vesicles such as exosomes are now recognized as key players in intercellular communication. Their role is influenced by the specific repertoires of proteins and lipids, which are enriched when they are generated as intraluminal vesicles (ILVs) in multivesicular endosomes. Here we report that a key component of small extracellular vesicles, the tetraspanin CD63, sorts cholesterol to ILVs, generating a pool that can be mobilized by the NPC1/2 complex, and exported via exosomes to recipient cells. In the absence of CD63, cholesterol is retrieved from the endosomes by actin-dependent vesicular transport, placing CD63 and cholesterol at the centre of a balance between inward and outward budding of endomembranes. These results establish CD63 as a lipid-sorting mechanism within endosomes, and show that ILVs and exosomes are alternative providers of cholesterol. Palmulli, Couty and colleagues show that the tetraspanin CD63 promotes accumulation of cholesterol in intraluminal vesicles (ILVs) at the expense of retrieval from endosomes; cholesterol stored in ILVs and exosomes is recovered in an NPC1-dependent manner.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141333675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-13DOI: 10.1038/s41556-024-01438-3
Meng Zhang, Martin Sjöström, Xiekui Cui, Adam Foye, Kyle Farh, Raunak Shrestha, Arian Lundberg, Ha X. Dang, Haolong Li, Phillip G. Febbo, Rahul Aggarwal, Joshi J. Alumkal, Eric J. Small, The SU2C/PCF West Coast Prostate Cancer Dream Team, Christopher A. Maher, Felix Y. Feng, David A. Quigley
Transcription factor (TF) proteins regulate gene activity by binding to regulatory regions, most importantly at gene promoters. Many genes have alternative promoters (APs) bound by distinct TFs. The role of differential TF activity at APs during tumour development is poorly understood. Here we show, using deep RNA sequencing in 274 biopsies of benign prostate tissue, localized prostate tumours and metastatic castration-resistant prostate cancer, that AP usage increases as tumours progress and APs are responsible for a disproportionate amount of tumour transcriptional activity. Expression of the androgen receptor (AR), the key driver of prostate tumour activity, is correlated with elevated AP usage. We identified AR, FOXA1 and MYC as potential drivers of AP activation. DNA methylation is a likely mechanism for AP activation during tumour progression and lineage plasticity. Our data suggest that prostate tumours activate APs to magnify the transcriptional impact of tumour drivers, including AR and MYC. With ultra-deep RNA sequencing, Zhang et al. report increased usage of alternative promoters driven by AR, FOXA1 and MYC during prostate cancer progression and suggest altered DNA methylation as a potential underlying mechanism.
{"title":"Integrative analysis of ultra-deep RNA-seq reveals alternative promoter usage as a mechanism of activating oncogenic programmes during prostate cancer progression","authors":"Meng Zhang, Martin Sjöström, Xiekui Cui, Adam Foye, Kyle Farh, Raunak Shrestha, Arian Lundberg, Ha X. Dang, Haolong Li, Phillip G. Febbo, Rahul Aggarwal, Joshi J. Alumkal, Eric J. Small, The SU2C/PCF West Coast Prostate Cancer Dream Team, Christopher A. Maher, Felix Y. Feng, David A. Quigley","doi":"10.1038/s41556-024-01438-3","DOIUrl":"10.1038/s41556-024-01438-3","url":null,"abstract":"Transcription factor (TF) proteins regulate gene activity by binding to regulatory regions, most importantly at gene promoters. Many genes have alternative promoters (APs) bound by distinct TFs. The role of differential TF activity at APs during tumour development is poorly understood. Here we show, using deep RNA sequencing in 274 biopsies of benign prostate tissue, localized prostate tumours and metastatic castration-resistant prostate cancer, that AP usage increases as tumours progress and APs are responsible for a disproportionate amount of tumour transcriptional activity. Expression of the androgen receptor (AR), the key driver of prostate tumour activity, is correlated with elevated AP usage. We identified AR, FOXA1 and MYC as potential drivers of AP activation. DNA methylation is a likely mechanism for AP activation during tumour progression and lineage plasticity. Our data suggest that prostate tumours activate APs to magnify the transcriptional impact of tumour drivers, including AR and MYC. With ultra-deep RNA sequencing, Zhang et al. report increased usage of alternative promoters driven by AR, FOXA1 and MYC during prostate cancer progression and suggest altered DNA methylation as a potential underlying mechanism.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-12DOI: 10.1038/s41556-024-01424-9
Fei Ma, Yaqiang Cao, Hansen Du, Fatima Zohra Braikia, Le Zong, Noah Ollikainen, Marc Bayer, Xiang Qiu, Bongsoo Park, Roshni Roy, Satabdi Nandi, Dimitra Sarantopoulou, Andrew Ziman, Aisha Haley Bianchi, Isabel Beerman, Keji Zhao, Rudolf Grosschedl, Ranjan Sen
The contribution of three-dimensional genome organization to physiological ageing is not well known. Here we show that large-scale chromatin reorganization distinguishes young and old bone marrow progenitor (pro-) B cells. These changes result in increased interactions at the compartment level and reduced interactions within topologically associated domains (TADs). The gene encoding Ebf1, a key B cell regulator, switches from compartment A to B with age. Genetically reducing Ebf1 recapitulates some features of old pro-B cells. TADs that are most reduced with age contain genes important for B cell development, including the immunoglobulin heavy chain (Igh) locus. Weaker intra-TAD interactions at Igh correlate with altered variable (V), diversity (D) and joining (J) gene recombination. Our observations implicate three-dimensional chromatin reorganization as a major driver of pro-B cell phenotypes that impair B lymphopoiesis with age. Ma, Cao et al. uncover dynamic changes of chromatin reorganization in progenitor B cells during ageing, associated with altered H3K27ac levels and expression of genes that are critical for B cell development.
三维基因组组织对生理性衰老的贡献尚不十分清楚。在这里，我们发现大规模染色质重组将年轻和衰老的骨髓祖（原）B细胞区分开来。这些变化导致区室水平的相互作用增加，拓扑相关域（TAD）内的相互作用减少。编码 B 细胞关键调节因子 Ebf1 的基因会随着年龄的增长从 A 区切换到 B 区。从基因上减少 Ebf1 可重现老年原 B 细胞的某些特征。随年龄增长而减少最多的 TAD 含有对 B 细胞发育很重要的基因，包括免疫球蛋白重链（Igh）基因座。Igh位点上TAD内相互作用的减弱与变异（V）、多样性（D）和连接（J）基因重组的改变有关。我们的观察结果表明，三维染色质重组是原 B 细胞表型的主要驱动因素，随着年龄的增长，原 B 细胞表型会损害 B 淋巴造血功能。
{"title":"Three-dimensional chromatin reorganization regulates B cell development during ageing","authors":"Fei Ma, Yaqiang Cao, Hansen Du, Fatima Zohra Braikia, Le Zong, Noah Ollikainen, Marc Bayer, Xiang Qiu, Bongsoo Park, Roshni Roy, Satabdi Nandi, Dimitra Sarantopoulou, Andrew Ziman, Aisha Haley Bianchi, Isabel Beerman, Keji Zhao, Rudolf Grosschedl, Ranjan Sen","doi":"10.1038/s41556-024-01424-9","DOIUrl":"10.1038/s41556-024-01424-9","url":null,"abstract":"The contribution of three-dimensional genome organization to physiological ageing is not well known. Here we show that large-scale chromatin reorganization distinguishes young and old bone marrow progenitor (pro-) B cells. These changes result in increased interactions at the compartment level and reduced interactions within topologically associated domains (TADs). The gene encoding Ebf1, a key B cell regulator, switches from compartment A to B with age. Genetically reducing Ebf1 recapitulates some features of old pro-B cells. TADs that are most reduced with age contain genes important for B cell development, including the immunoglobulin heavy chain (Igh) locus. Weaker intra-TAD interactions at Igh correlate with altered variable (V), diversity (D) and joining (J) gene recombination. Our observations implicate three-dimensional chromatin reorganization as a major driver of pro-B cell phenotypes that impair B lymphopoiesis with age. Ma, Cao et al. uncover dynamic changes of chromatin reorganization in progenitor B cells during ageing, associated with altered H3K27ac levels and expression of genes that are critical for B cell development.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01424-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11DOI: 10.1038/s41556-024-01426-7
Christina M. Ferrer, Hyo Min Cho, Ruben Boon, Tiziano Bernasocchi, Lai Ping Wong, Murat Cetinbas, Elizabeth R. Haggerty, Irene Mitsiades, Gregory R. Wojtkiewicz, Daniel E. McLoughlin, Reem Aboushousha, Hend Abdelhamid, Sita Kugel, Esther Rheinbay, Ruslan Sadreyev, Dejan Juric, Yvonne M. W. Janssen-Heininger, Raul Mostoslavsky
Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial–mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment. With a shRNA targeted screen, Ferrer, Cho, Boon et al. identify a role for Gstt1 in enhancing epithelial–mesenchymal transition and disseminated tumour cell features in a subset of slow-cycling cells, thereby facilitating metastatic progression.
{"title":"The glutathione S-transferase Gstt1 drives survival and dissemination in metastases","authors":"Christina M. Ferrer, Hyo Min Cho, Ruben Boon, Tiziano Bernasocchi, Lai Ping Wong, Murat Cetinbas, Elizabeth R. Haggerty, Irene Mitsiades, Gregory R. Wojtkiewicz, Daniel E. McLoughlin, Reem Aboushousha, Hend Abdelhamid, Sita Kugel, Esther Rheinbay, Ruslan Sadreyev, Dejan Juric, Yvonne M. W. Janssen-Heininger, Raul Mostoslavsky","doi":"10.1038/s41556-024-01426-7","DOIUrl":"10.1038/s41556-024-01426-7","url":null,"abstract":"Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial–mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment. With a shRNA targeted screen, Ferrer, Cho, Boon et al. identify a role for Gstt1 in enhancing epithelial–mesenchymal transition and disseminated tumour cell features in a subset of slow-cycling cells, thereby facilitating metastatic progression.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141304557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-10DOI: 10.1038/s41556-024-01428-5
Lele Wu, Zheng Zhao, Yong Jae Shin, Yiyun Yin, Anandhkumar Raju, Thamil Selvan Vaiyapuri, Khaireen Idzham, Miseol Son, Yeri Lee, Jason K. Sa, Joelle Yi Heng Chua, Bilal Unal, You Zhai, Wenhua Fan, Lijie Huang, Huimin Hu, Jayantha Gunaratne, Do-Hyun Nam, Tao Jiang, Vinay Tergaonkar
Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA–RNA-binding protein complex LOC–DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood–brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA–RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body. Wu, Zhao, Shin and Yin show that the RNA–RNA-binding protein complex LOC–DHX15 drives microglia infiltration into the tumour microenvironment in glioblastoma and suggest targeting this complex as a potential treatment strategy.
{"title":"Tumour microenvironment programming by an RNA–RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma","authors":"Lele Wu, Zheng Zhao, Yong Jae Shin, Yiyun Yin, Anandhkumar Raju, Thamil Selvan Vaiyapuri, Khaireen Idzham, Miseol Son, Yeri Lee, Jason K. Sa, Joelle Yi Heng Chua, Bilal Unal, You Zhai, Wenhua Fan, Lijie Huang, Huimin Hu, Jayantha Gunaratne, Do-Hyun Nam, Tao Jiang, Vinay Tergaonkar","doi":"10.1038/s41556-024-01428-5","DOIUrl":"10.1038/s41556-024-01428-5","url":null,"abstract":"Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA–RNA-binding protein complex LOC–DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood–brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA–RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body. Wu, Zhao, Shin and Yin show that the RNA–RNA-binding protein complex LOC–DHX15 drives microglia infiltration into the tumour microenvironment in glioblastoma and suggest targeting this complex as a potential treatment strategy.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01428-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-10DOI: 10.1038/s41556-024-01425-8
Toshitaka Nakamura, Marcus Conrad
Ferroptosis is a distinct lipid peroxidation-dependent form of necrotic cell death. This process has been increasingly contemplated as a new target for cancer therapy because of an intrinsic or acquired ferroptosis vulnerability in difficult-to-treat cancers and tumour microenvironments. Here we review recent advances in our understanding of the molecular mechanisms that underlie ferroptosis and highlight available tools for the modulation of ferroptosis sensitivity in cancer cells and communication with immune cells within the tumour microenvironment. We further discuss how these new insights into ferroptosis-activating pathways can become new armouries in the fight against cancer. Ferroptosis is a form of cell death that is characterized by morphological abnormalities of mitochondria and the overwhelming peroxidation of phospholipids. Certain tumours are susceptible to ferroptosis, which could be exploited to treat cancers.
{"title":"Exploiting ferroptosis vulnerabilities in cancer","authors":"Toshitaka Nakamura, Marcus Conrad","doi":"10.1038/s41556-024-01425-8","DOIUrl":"10.1038/s41556-024-01425-8","url":null,"abstract":"Ferroptosis is a distinct lipid peroxidation-dependent form of necrotic cell death. This process has been increasingly contemplated as a new target for cancer therapy because of an intrinsic or acquired ferroptosis vulnerability in difficult-to-treat cancers and tumour microenvironments. Here we review recent advances in our understanding of the molecular mechanisms that underlie ferroptosis and highlight available tools for the modulation of ferroptosis sensitivity in cancer cells and communication with immune cells within the tumour microenvironment. We further discuss how these new insights into ferroptosis-activating pathways can become new armouries in the fight against cancer. Ferroptosis is a form of cell death that is characterized by morphological abnormalities of mitochondria and the overwhelming peroxidation of phospholipids. Certain tumours are susceptible to ferroptosis, which could be exploited to treat cancers.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141298984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-07DOI: 10.1038/s41556-024-01430-x
Qiushuang Wu, Sohail F. Tavazoie
Aminoacyl-tRNA synthetases can promote or suppress cancer progression by regulating codon-dependent translation. A study now shows that valine aminoacyl-tRNA synthetase (VARS) promotes therapeutic resistance of melanoma to MAPK pathway inhibitors by enhancing translation of valine-enriched genes, including the fatty acid oxidation gene HADH.
{"title":"Translational control by VARS in melanoma","authors":"Qiushuang Wu, Sohail F. Tavazoie","doi":"10.1038/s41556-024-01430-x","DOIUrl":"10.1038/s41556-024-01430-x","url":null,"abstract":"Aminoacyl-tRNA synthetases can promote or suppress cancer progression by regulating codon-dependent translation. A study now shows that valine aminoacyl-tRNA synthetase (VARS) promotes therapeutic resistance of melanoma to MAPK pathway inhibitors by enhancing translation of valine-enriched genes, including the fatty acid oxidation gene HADH.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-07DOI: 10.1038/s41556-024-01431-w
Julia Batki, Sara Hetzel, Dennis Schifferl, Adriano Bolondi, Maria Walther, Lars Wittler, Stefanie Grosswendt, Bernhard G. Herrmann, Alexander Meissner
Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, all extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if extraembryonic cells persist into later development. Here we developed a two-colour lineage-tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of the original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighbouring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild-type gut, whereas they persist and differentiate further in p53-mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo. Batki, Hetzel et al. report a lineage-tracing strategy to track extraembryonic gut endoderm cells over development. They find that these cells are eventually eliminated in a p53-dependent manner and neighbouring embryonic cells clear their remnants.
尽管发育起源不同，但小鼠的胚外细胞对肠道内胚层有贡献，并在转录上与胚胎细胞相似。值得注意的是，所有胚外祖细胞都有一个非规范表观基因组，这就提出了几个相关的问题，包括该表观是否会重置以匹配胚胎调控，以及胚外细胞是否会持续到后期发育。在这里，我们开发了一种双色系追踪策略，以追踪和分离胚外细胞。我们发现，胚外肠道细胞显示出对其发育起源的大量记忆，包括保留原始 DNA 甲基化景观和由此产生的转录特征。此外，我们还发现胚外肠道细胞会发生程序性细胞死亡，邻近的胚胎细胞会通过非专业的吞噬作用清除其残余。到妊娠中期，我们在野生型肠道中不再检测到胚外细胞，而在p53突变型胚胎中，胚外细胞持续存在并进一步分化。我们的研究为了解胚外细胞在胚胎内的分子和发育命运提供了重要信息。
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