Pub Date : 2024-09-12DOI: 10.1038/s41556-024-01508-6
Xiaoxin Hao, Yichao Shen, Jun Liu, Angela Alexander, Ling Wu, Zhan Xu, Liqun Yu, Yang Gao, Fengshuo Liu, Hilda L. Chan, Che-Hsing Li, Yunfeng Ding, Weijie Zhang, David G. Edwards, Nan Chen, Azadeh Nasrazadani, Naoto T. Ueno, Bora Lim, Xiang H.-F. Zhang
Solid tumours induce systemic immunosuppression that involves myeloid and T cells. B cell-related mechanisms remain relatively understudied. Here we discover two distinct patterns of tumour-induced B cell abnormality (TiBA; TiBA-1 and TiBA-2), both associated with abnormal myelopoiesis in the bone marrow. TiBA-1 probably results from the niche competition between pre-progenitor-B cells and myeloid progenitors, leading to a global reduction in downstream B cells. TiBA-2 is characterized by systemic accumulation of a unique early B cell population, driven by interaction with excessive neutrophils. Importantly, TiBA-2-associated early B cells foster the systemic accumulation of exhaustion-like T cells. Myeloid and B cells from the peripheral blood of patients with triple-negative breast cancer recapitulate the TiBA subtypes, and the distinct TiBA profile correlates with pathologic complete responses to standard-of-care immunotherapy. This study underscores the inter-patient diversity of tumour-induced systemic changes and emphasizes the need for treatments tailored to different B and myeloid cell abnormalities. Hao, Shen and colleagues identify and characterize two distinct types of myeloid–B cell interaction that may signal solid tumour-induced immunosuppression and can correlate with complete responses to immunotherapy in patients with breast cancer.
实体瘤引起的全身免疫抑制涉及骨髓细胞和 T 细胞。与 B 细胞相关的机制研究相对较少。在这里，我们发现了两种不同的肿瘤诱导 B 细胞异常（TiBA；TiBA-1 和 TiBA-2）模式，这两种模式都与骨髓中的异常骨髓造血有关。TiBA-1 可能是由于前祖细胞-B 细胞和骨髓祖细胞之间的生态位竞争，导致下游 B 细胞全面减少。TiBA-2 的特点是，在与过多中性粒细胞相互作用的驱动下，一种独特的早期 B 细胞群在全身积聚。重要的是，与TiBA-2相关的早期B细胞会促进衰竭样T细胞的系统性积累。三阴性乳腺癌患者外周血中的骨髓细胞和B细胞再现了TiBA亚型，独特的TiBA特征与标准护理免疫疗法的病理完全反应相关。这项研究强调了肿瘤诱导的全身性变化在患者间的多样性，并强调了针对不同B细胞和骨髓细胞异常进行治疗的必要性。
{"title":"Solid tumour-induced systemic immunosuppression involves dichotomous myeloid–B cell interactions","authors":"Xiaoxin Hao, Yichao Shen, Jun Liu, Angela Alexander, Ling Wu, Zhan Xu, Liqun Yu, Yang Gao, Fengshuo Liu, Hilda L. Chan, Che-Hsing Li, Yunfeng Ding, Weijie Zhang, David G. Edwards, Nan Chen, Azadeh Nasrazadani, Naoto T. Ueno, Bora Lim, Xiang H.-F. Zhang","doi":"10.1038/s41556-024-01508-6","DOIUrl":"10.1038/s41556-024-01508-6","url":null,"abstract":"Solid tumours induce systemic immunosuppression that involves myeloid and T cells. B cell-related mechanisms remain relatively understudied. Here we discover two distinct patterns of tumour-induced B cell abnormality (TiBA; TiBA-1 and TiBA-2), both associated with abnormal myelopoiesis in the bone marrow. TiBA-1 probably results from the niche competition between pre-progenitor-B cells and myeloid progenitors, leading to a global reduction in downstream B cells. TiBA-2 is characterized by systemic accumulation of a unique early B cell population, driven by interaction with excessive neutrophils. Importantly, TiBA-2-associated early B cells foster the systemic accumulation of exhaustion-like T cells. Myeloid and B cells from the peripheral blood of patients with triple-negative breast cancer recapitulate the TiBA subtypes, and the distinct TiBA profile correlates with pathologic complete responses to standard-of-care immunotherapy. This study underscores the inter-patient diversity of tumour-induced systemic changes and emphasizes the need for treatments tailored to different B and myeloid cell abnormalities. Hao, Shen and colleagues identify and characterize two distinct types of myeloid–B cell interaction that may signal solid tumour-induced immunosuppression and can correlate with complete responses to immunotherapy in patients with breast cancer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1971-1983"},"PeriodicalIF":17.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170869","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 : 2024-09-12DOI: 10.1038/s41556-024-01504-w
Zhe Wang
{"title":"Ferroptosis disseminates afar in development","authors":"Zhe Wang","doi":"10.1038/s41556-024-01504-w","DOIUrl":"10.1038/s41556-024-01504-w","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1374-1374"},"PeriodicalIF":17.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174410","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 : 2024-09-11DOI: 10.1038/s41556-024-01493-w
Aleksander T. Szczurek, Emilia Dimitrova, Jessica R. Kelley, Neil P. Blackledge, Robert J. Klose
The Polycomb system has fundamental roles in regulating gene expression during mammalian development. However, how it controls transcription to enable gene repression has remained enigmatic. Here, using rapid degron-based depletion coupled with live-cell transcription imaging and single-particle tracking, we show how the Polycomb system controls transcription in single cells. We discover that the Polycomb system is not a constitutive block to transcription but instead sustains a long-lived deep promoter OFF state, which limits the frequency with which the promoter can enter into a transcribing state. We demonstrate that Polycomb sustains this deep promoter OFF state by counteracting the binding of factors that enable early transcription pre-initiation complex formation and show that this is necessary for gene repression. Together, these important discoveries provide a rationale for how the Polycomb system controls transcription and suggests a universal mechanism that could enable the Polycomb system to constrain transcription across diverse cellular contexts. Combining degron-based depletion with live-cell transcription imaging and single-particle tracking, Szczurek et al. show that Polycomb keeps promoters in an OFF state by restricting the formation of the pre-initiation complex.
{"title":"The Polycomb system sustains promoters in a deep OFF state by limiting pre-initiation complex formation to counteract transcription","authors":"Aleksander T. Szczurek, Emilia Dimitrova, Jessica R. Kelley, Neil P. Blackledge, Robert J. Klose","doi":"10.1038/s41556-024-01493-w","DOIUrl":"10.1038/s41556-024-01493-w","url":null,"abstract":"The Polycomb system has fundamental roles in regulating gene expression during mammalian development. However, how it controls transcription to enable gene repression has remained enigmatic. Here, using rapid degron-based depletion coupled with live-cell transcription imaging and single-particle tracking, we show how the Polycomb system controls transcription in single cells. We discover that the Polycomb system is not a constitutive block to transcription but instead sustains a long-lived deep promoter OFF state, which limits the frequency with which the promoter can enter into a transcribing state. We demonstrate that Polycomb sustains this deep promoter OFF state by counteracting the binding of factors that enable early transcription pre-initiation complex formation and show that this is necessary for gene repression. Together, these important discoveries provide a rationale for how the Polycomb system controls transcription and suggests a universal mechanism that could enable the Polycomb system to constrain transcription across diverse cellular contexts. Combining degron-based depletion with live-cell transcription imaging and single-particle tracking, Szczurek et al. show that Polycomb keeps promoters in an OFF state by restricting the formation of the pre-initiation complex.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1700-1711"},"PeriodicalIF":17.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01493-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170870","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}
Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms. Zhang, Liu and colleagues identify and characterize cell death in rapidly proliferating CD8+ T cells resulting from excessive ammonia accumulation and subsequent lysosomal dysfunction and mitochondrial damage.
氨被认为是一种细胞毒素，血液中氨的增加会损害细胞功能。然而，这种毒素是否以及如何在病理生理条件下引发细胞死亡仍不清楚。在这里，我们发现氨在效应 T 细胞中诱导了一种不同形式的细胞死亡。我们发现，快速增殖的 T 细胞利用谷氨酰胺溶解作用在线粒体中释放氨，然后将氨转运到溶酶体并储存起来。过量的氨积累会增加溶酶体的 pH 值，导致溶酶体氨储存终止和氨反流进入线粒体，从而导致线粒体损伤和细胞死亡，其特征是溶酶体碱化、线粒体肿胀和自噬通量受损。抑制谷氨酰胺溶解或阻断溶酶体碱化可防止氨诱导的 T 细胞死亡，并改善基于 T 细胞的抗肿瘤免疫疗法。这些发现确定了一种不同于以往已知机制的独特细胞死亡形式。
{"title":"Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells","authors":"Huafeng Zhang, Jincheng Liu, Wu Yuan, Qian Zhang, Xiao Luo, Yonggang Li, Yue’e Peng, Jingyu Feng, Xiaoyu Liu, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang","doi":"10.1038/s41556-024-01503-x","DOIUrl":"10.1038/s41556-024-01503-x","url":null,"abstract":"Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms. Zhang, Liu and colleagues identify and characterize cell death in rapidly proliferating CD8+ T cells resulting from excessive ammonia accumulation and subsequent lysosomal dysfunction and mitochondrial damage.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1892-1902"},"PeriodicalIF":17.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170871","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 : 2024-09-11DOI: 10.1038/s41556-024-01501-z
Markus F. Schliffka, Julien G. Dumortier, Diane Pelzer, Arghyadip Mukherjee, Jean-Léon Maître
During preimplantation development, mouse embryos form a fluid-filled lumen. Pressurized fluid fractures cell–cell contacts and accumulates into pockets, which coarsen into a single lumen. How the embryo controls intercellular fluid movement during coarsening is unknown. Here we report inverse blebs growing into cells at adhesive contacts. Throughout the embryo we observed hundreds of inverse blebs, each filling with intercellular fluid and retracting within a minute. Inverse blebs grow due to pressure build-up resulting from fluid accumulation and cell–cell adhesion, which locally confines fluid. Inverse blebs retract due to actomyosin contraction, practically pushing fluid within the intercellular space. Importantly, inverse blebs occur infrequently at contacts formed by multiple cells, which effectively serve as fluid sinks. Manipulation of the embryo topology reveals that without sinks inverse blebs pump fluid into one another in futile cycles. We propose that inverse blebs operate as hydraulic pumps to promote luminal coarsening, thereby constituting an instrument used by cells to control fluid movement. Schliffka et al. show that in the early mouse embryo, hemispherical intrusions, or inverse blebs, grow into cells at cell–cell adhesion sites in response to luminal fluid accumulation and pressure build-up, and may serve as pumps moving fluid into hydraulic sinks.
{"title":"Inverse blebs operate as hydraulic pumps during mouse blastocyst formation","authors":"Markus F. Schliffka, Julien G. Dumortier, Diane Pelzer, Arghyadip Mukherjee, Jean-Léon Maître","doi":"10.1038/s41556-024-01501-z","DOIUrl":"10.1038/s41556-024-01501-z","url":null,"abstract":"During preimplantation development, mouse embryos form a fluid-filled lumen. Pressurized fluid fractures cell–cell contacts and accumulates into pockets, which coarsen into a single lumen. How the embryo controls intercellular fluid movement during coarsening is unknown. Here we report inverse blebs growing into cells at adhesive contacts. Throughout the embryo we observed hundreds of inverse blebs, each filling with intercellular fluid and retracting within a minute. Inverse blebs grow due to pressure build-up resulting from fluid accumulation and cell–cell adhesion, which locally confines fluid. Inverse blebs retract due to actomyosin contraction, practically pushing fluid within the intercellular space. Importantly, inverse blebs occur infrequently at contacts formed by multiple cells, which effectively serve as fluid sinks. Manipulation of the embryo topology reveals that without sinks inverse blebs pump fluid into one another in futile cycles. We propose that inverse blebs operate as hydraulic pumps to promote luminal coarsening, thereby constituting an instrument used by cells to control fluid movement. Schliffka et al. show that in the early mouse embryo, hemispherical intrusions, or inverse blebs, grow into cells at cell–cell adhesion sites in response to luminal fluid accumulation and pressure build-up, and may serve as pumps moving fluid into hydraulic sinks.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1669-1677"},"PeriodicalIF":17.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170873","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}
The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth. Guo, Hong et al. report that TET2 condensation maintains proper DNA demethylation at specific genomic loci, which can be targeted to alter gene expression and impair leukaemia growth.
十-十一易位（TET）二氧合酶家族在细胞分裂和品系分化过程中维持稳定的局部 DNA 去甲基化。作为 TET 酶的主要催化产物，5-羟甲基胞嘧啶以组织依赖的方式选择性地富集在特定的基因组区域，如增强子。然而，这种选择性的内在机制仍未解决。在这里，我们揭示了 TET2 中的一个低复杂性插入结构域，它能促进 TET2 与表观遗传调节剂（如 UTX 和 MLL4）的生物分子缩聚。这种共同凝结为 DNA 的精确去甲基化创造了有利的染色质环境。破坏低复杂性插入介导的缩聚会改变 TET2 的基因组结合，从而导致杂乱的 DNA 去甲基化和基因组重组。这些变化会影响与白血病发生有关的关键基因的表达，从而抑制白血病细胞的增殖。总之，这项研究证实了 TET2 冷凝在协调精确的 DNA 去甲基化和基因转录以支持肿瘤细胞生长方面的关键作用。
{"title":"Perturbing TET2 condensation promotes aberrant genome-wide DNA methylation and curtails leukaemia cell growth","authors":"Lei Guo, Tingting Hong, Yi-Tsang Lee, Xue Hu, Guokai Pan, Rongjie Zhao, Yuhan Yang, Jingwen Yang, Xiaoli Cai, Logan Rivera, Jie Liang, Rui Wang, Yaling Dou, Srikanth Kodali, Wenbo Li, Leng Han, Bruno Di Stefano, Yubin Zhou, Jia Li, Yun Huang","doi":"10.1038/s41556-024-01496-7","DOIUrl":"10.1038/s41556-024-01496-7","url":null,"abstract":"The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth. Guo, Hong et al. report that TET2 condensation maintains proper DNA demethylation at specific genomic loci, which can be targeted to alter gene expression and impair leukaemia growth.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2154-2167"},"PeriodicalIF":17.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158752","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 : 2024-09-05DOI: 10.1038/s41556-024-01500-0
Christian de Caestecker, Ian G. Macara
Despite decades of research, apical sorting of epithelial membrane proteins remains incompletely understood. We noted that apical cytoplasmic domains are smaller than those of basolateral proteins; however, the reason for this discrepancy is unknown. Here we used a synthetic biology approach to investigate whether a size barrier at the Golgi apparatus might hinder apical sorting of proteins with large cytoplasmic tails. We focused on Crb3, Ace2 and Muc1 as representative apical proteins with short cytoplasmic tails. By incorporating a streptavidin-binding peptide, these proteins can be trapped in the endoplasmic reticulum until addition of biotin, which triggers synchronous release to the Golgi and subsequent transport to the apical cortex. Strikingly, increasing the size of their cytoplasmic domains caused partial mislocalization to the basolateral cortex and significantly delayed Golgi departure. Moreover, N-glycosylation of ‘large’ Crb3 was delayed, and ‘small’ Crb3 segregated into spatially distinct Golgi regions. Biologically, Crb3 forms a complex through its cytoplasmic tail with the Pals1 protein, which could also delay departure, but although associated at the endoplasmic reticulum and Golgi, Pals1 disassociated before Crb3 departure. Notably, a non-dissociable mutant Pals1 hampered the exit of Crb3. We conclude that, unexpectedly, a size filter at the Golgi facilitates apical sorting of proteins with small cytoplasmic domains and that timely release of Pals1, to reduce cytoplasmic domain size, is essential for normal Crb3 sorting. de Caestecker and Macara study apical sorting of proteins with varying cytoplasmic tail length in epithelial cells. They propose that a size filter at the Golgi facilitates apical sorting of proteins with small cytoplasmic domains.
{"title":"A size filter at the Golgi regulates apical membrane protein sorting","authors":"Christian de Caestecker, Ian G. Macara","doi":"10.1038/s41556-024-01500-0","DOIUrl":"10.1038/s41556-024-01500-0","url":null,"abstract":"Despite decades of research, apical sorting of epithelial membrane proteins remains incompletely understood. We noted that apical cytoplasmic domains are smaller than those of basolateral proteins; however, the reason for this discrepancy is unknown. Here we used a synthetic biology approach to investigate whether a size barrier at the Golgi apparatus might hinder apical sorting of proteins with large cytoplasmic tails. We focused on Crb3, Ace2 and Muc1 as representative apical proteins with short cytoplasmic tails. By incorporating a streptavidin-binding peptide, these proteins can be trapped in the endoplasmic reticulum until addition of biotin, which triggers synchronous release to the Golgi and subsequent transport to the apical cortex. Strikingly, increasing the size of their cytoplasmic domains caused partial mislocalization to the basolateral cortex and significantly delayed Golgi departure. Moreover, N-glycosylation of ‘large’ Crb3 was delayed, and ‘small’ Crb3 segregated into spatially distinct Golgi regions. Biologically, Crb3 forms a complex through its cytoplasmic tail with the Pals1 protein, which could also delay departure, but although associated at the endoplasmic reticulum and Golgi, Pals1 disassociated before Crb3 departure. Notably, a non-dissociable mutant Pals1 hampered the exit of Crb3. We conclude that, unexpectedly, a size filter at the Golgi facilitates apical sorting of proteins with small cytoplasmic domains and that timely release of Pals1, to reduce cytoplasmic domain size, is essential for normal Crb3 sorting. de Caestecker and Macara study apical sorting of proteins with varying cytoplasmic tail length in epithelial cells. They propose that a size filter at the Golgi facilitates apical sorting of proteins with small cytoplasmic domains.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1678-1690"},"PeriodicalIF":17.3,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138031","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}
Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer. Tamagawa, Fujii et al. demonstrate that squamous differentiation in human pancreatic cancer can be attributed to TP63-mediated lineage conversion and epigenetic reprogramming that depends upon a hypoxic and Wnt-defective niche.
{"title":"Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma","authors":"Hiroki Tamagawa, Masayuki Fujii, Kazuhiro Togasaki, Takashi Seino, Shintaro Kawasaki, Ai Takano, Kohta Toshimitsu, Sirirat Takahashi, Yuki Ohta, Mami Matano, Kenta Kawasaki, Yujiro Machida, Shigeki Sekine, Akihito Machinaga, Ken Sasai, Yuzo Kodama, Nobuyuki Kakiuchi, Seishi Ogawa, Tomonori Hirano, Hiroshi Seno, Minoru Kitago, Yuko Kitagawa, Eisuke Iwasaki, Takanori Kanai, Toshiro Sato","doi":"10.1038/s41556-024-01498-5","DOIUrl":"10.1038/s41556-024-01498-5","url":null,"abstract":"Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer. Tamagawa, Fujii et al. demonstrate that squamous differentiation in human pancreatic cancer can be attributed to TP63-mediated lineage conversion and epigenetic reprogramming that depends upon a hypoxic and Wnt-defective niche.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1759-1772"},"PeriodicalIF":17.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130879","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}
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