Pub Date : 2024-08-22DOI: 10.1016/j.cell.2024.07.037
Daniel Hollern
Two recent studies reveal that the extent of fitness or anergy in tumor-associated memory B cells is vital to anti-tumor immune response, cancer patient survival, and response to immune therapy. The impact of these seminal findings demonstrates the untapped potential for using B cells to combat the lethality of cancer.
最近的两项研究揭示,肿瘤相关记忆 B 细胞的适存或失活程度对抗肿瘤免疫反应、癌症患者的存活以及对免疫疗法的反应至关重要。这些开创性发现的影响表明,利用 B 细胞对抗癌症致命性的潜力尚未开发。
{"title":"Memory B cell fitness and anergy has significant links to cancer lethality","authors":"Daniel Hollern","doi":"10.1016/j.cell.2024.07.037","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.037","url":null,"abstract":"<p>Two recent studies reveal that the extent of fitness or anergy in tumor-associated memory B cells is vital to anti-tumor immune response, cancer patient survival, and response to immune therapy. The impact of these seminal findings demonstrates the untapped potential for using B cells to combat the lethality of cancer.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023043","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 : 2024-08-22DOI: 10.1016/j.cell.2024.08.015
George Mountoufaris, Aditya Nair, Bin Yang, Dong-Wook Kim, Amit Vinograd, Samuel Kim, Scott W Linderman, David J Anderson
Internal states drive survival behaviors, but their neural implementation is poorly understood. Recently, we identified a line attractor in the ventromedial hypothalamus (VMH) that represents a state of aggressiveness. Line attractors can be implemented by recurrent connectivity or neuromodulatory signaling, but evidence for the latter is scant. Here, we demonstrate that neuropeptidergic signaling is necessary for line attractor dynamics in this system by using cell-type-specific CRISPR-Cas9-based gene editing combined with single-cell calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1+ neurons that control aggression diminished attack, reduced persistent neural activity, and eliminated line attractor dynamics while only slightly reducing overall neural activity and sex- or behavior-specific tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor in mammals. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.
{"title":"A line attractor encoding a persistent internal state requires neuropeptide signaling.","authors":"George Mountoufaris, Aditya Nair, Bin Yang, Dong-Wook Kim, Amit Vinograd, Samuel Kim, Scott W Linderman, David J Anderson","doi":"10.1016/j.cell.2024.08.015","DOIUrl":"10.1016/j.cell.2024.08.015","url":null,"abstract":"<p><p>Internal states drive survival behaviors, but their neural implementation is poorly understood. Recently, we identified a line attractor in the ventromedial hypothalamus (VMH) that represents a state of aggressiveness. Line attractors can be implemented by recurrent connectivity or neuromodulatory signaling, but evidence for the latter is scant. Here, we demonstrate that neuropeptidergic signaling is necessary for line attractor dynamics in this system by using cell-type-specific CRISPR-Cas9-based gene editing combined with single-cell calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1<sup>+</sup> neurons that control aggression diminished attack, reduced persistent neural activity, and eliminated line attractor dynamics while only slightly reducing overall neural activity and sex- or behavior-specific tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor in mammals. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":45.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079285","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 : 2024-08-22DOI: 10.1016/j.cell.2024.07.036
Chris Xu, Maiken Nedergaard, Deborah J. Fowell, Peter Friedl, Na Ji
Multiphoton fluorescence microscopy (MPFM) has been a game-changer for optical imaging, particularly for studying biological tissues deep within living organisms. MPFM overcomes the strong scattering of light in heterogeneous tissue by utilizing nonlinear excitation that confines fluorescence emission mostly to the microscope focal volume. This enables high-resolution imaging deep within intact tissue and has opened new avenues for structural and functional studies. MPFM has found widespread applications and has led to numerous scientific discoveries and insights into complex biological processes. Today, MPFM is an indispensable tool in many research communities. Its versatility and effectiveness make it a go-to technique for researchers investigating biological phenomena at the cellular and subcellular levels in their native environments. In this Review, the principles, implementations, capabilities, and limitations of MPFM are presented. Three application areas of MPFM, neuroscience, cancer biology, and immunology, are reviewed in detail and serve as examples for applying MPFM to biological research.
{"title":"Multiphoton fluorescence microscopy for in vivo imaging","authors":"Chris Xu, Maiken Nedergaard, Deborah J. Fowell, Peter Friedl, Na Ji","doi":"10.1016/j.cell.2024.07.036","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.036","url":null,"abstract":"<p>Multiphoton fluorescence microscopy (MPFM) has been a game-changer for optical imaging, particularly for studying biological tissues deep within living organisms. MPFM overcomes the strong scattering of light in heterogeneous tissue by utilizing nonlinear excitation that confines fluorescence emission mostly to the microscope focal volume. This enables high-resolution imaging deep within intact tissue and has opened new avenues for structural and functional studies. MPFM has found widespread applications and has led to numerous scientific discoveries and insights into complex biological processes. Today, MPFM is an indispensable tool in many research communities. Its versatility and effectiveness make it a go-to technique for researchers investigating biological phenomena at the cellular and subcellular levels in their native environments. In this Review, the principles, implementations, capabilities, and limitations of MPFM are presented. Three application areas of MPFM, neuroscience, cancer biology, and immunology, are reviewed in detail and serve as examples for applying MPFM to biological research.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023040","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 : 2024-08-22DOI: 10.1016/j.cell.2024.07.040
Longqi Liu, Ao Chen, Yuxiang Li, Jan Mulder, Holger Heyn, Xun Xu
The completion of the Human Genome Project has provided a foundational blueprint for understanding human life. Nonetheless, understanding the intricate mechanisms through which our genetic blueprint is involved in disease or orchestrates development across temporal and spatial dimensions remains a profound scientific challenge. Recent breakthroughs in cellular omics technologies have paved new pathways for understanding the regulation of genomic elements and the relationship between gene expression, cellular functions, and cell fate determination. The advent of spatial omics technologies, encompassing both imaging and sequencing-based methodologies, has enabled a comprehensive understanding of biological processes from a cellular ecosystem perspective. This review offers an updated overview of how spatial omics has advanced our understanding of the translation of genetic information into cellular heterogeneity and tissue structural organization and their dynamic changes over time. It emphasizes the discovery of various biological phenomena, related to organ functionality, embryogenesis, species evolution, and the pathogenesis of diseases.
{"title":"Spatiotemporal omics for biology and medicine","authors":"Longqi Liu, Ao Chen, Yuxiang Li, Jan Mulder, Holger Heyn, Xun Xu","doi":"10.1016/j.cell.2024.07.040","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.040","url":null,"abstract":"<p>The completion of the Human Genome Project has provided a foundational blueprint for understanding human life. Nonetheless, understanding the intricate mechanisms through which our genetic blueprint is involved in disease or orchestrates development across temporal and spatial dimensions remains a profound scientific challenge. Recent breakthroughs in cellular omics technologies have paved new pathways for understanding the regulation of genomic elements and the relationship between gene expression, cellular functions, and cell fate determination. The advent of spatial omics technologies, encompassing both imaging and sequencing-based methodologies, has enabled a comprehensive understanding of biological processes from a cellular ecosystem perspective. This review offers an updated overview of how spatial omics has advanced our understanding of the translation of genetic information into cellular heterogeneity and tissue structural organization and their dynamic changes over time. It emphasizes the discovery of various biological phenomena, related to organ functionality, embryogenesis, species evolution, and the pathogenesis of diseases.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023041","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 : 2024-08-22DOI: 10.1016/j.cell.2024.07.035
Jennifer E. Rood, Anna Hupalowska, Aviv Regev
Comprehensively charting the biologically causal circuits that govern the phenotypic space of human cells has often been viewed as an insurmountable challenge. However, in the last decade, a suite of interleaved experimental and computational technologies has arisen that is making this fundamental goal increasingly tractable. Pooled CRISPR-based perturbation screens with high-content molecular and/or image-based readouts are now enabling researchers to probe, map, and decipher genetically causal circuits at increasing scale. This scale is now eminently suitable for the deployment of artificial intelligence and machine learning (AI/ML) to both direct further experiments and to predict or generate information that was not—and sometimes cannot—be gathered experimentally. By combining and iterating those through experiments that are designed for inference, we now envision a Perturbation Cell Atlas as a generative causal foundation model to unify human cell biology.
{"title":"Toward a foundation model of causal cell and tissue biology with a Perturbation Cell and Tissue Atlas","authors":"Jennifer E. Rood, Anna Hupalowska, Aviv Regev","doi":"10.1016/j.cell.2024.07.035","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.035","url":null,"abstract":"<p>Comprehensively charting the biologically causal circuits that govern the phenotypic space of human cells has often been viewed as an insurmountable challenge. However, in the last decade, a suite of interleaved experimental and computational technologies has arisen that is making this fundamental goal increasingly tractable. Pooled CRISPR-based perturbation screens with high-content molecular and/or image-based readouts are now enabling researchers to probe, map, and decipher genetically causal circuits at increasing scale. This scale is now eminently suitable for the deployment of artificial intelligence and machine learning (AI/ML) to both direct further experiments and to predict or generate information that was not—and sometimes cannot—be gathered experimentally. By combining and iterating those through experiments that are designed for inference, we now envision a Perturbation Cell Atlas as a generative causal foundation model to unify human cell biology.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023049","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 : 2024-08-22DOI: 10.1016/j.cell.2024.07.041
Daniel R. Hochbaum, Lauren Hulshof, Amanda Urke, Wengang Wang, Alexandra C. Dubinsky, Hannah C. Farnsworth, Richard Hakim, Sherry Lin, Giona Kleinberg, Keiramarie Robertson, Canaria Park, Alyssa Solberg, Yechan Yang, Caroline Baynard, Naeem M. Nadaf, Celia C. Beron, Allison E. Girasole, Lynne Chantranupong, Marissa D. Cortopassi, Shannon Prouty, Bernardo L. Sabatini
Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone—a regulator of metabolism in many peripheral organs—directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.
{"title":"Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration","authors":"Daniel R. Hochbaum, Lauren Hulshof, Amanda Urke, Wengang Wang, Alexandra C. Dubinsky, Hannah C. Farnsworth, Richard Hakim, Sherry Lin, Giona Kleinberg, Keiramarie Robertson, Canaria Park, Alyssa Solberg, Yechan Yang, Caroline Baynard, Naeem M. Nadaf, Celia C. Beron, Allison E. Girasole, Lynne Chantranupong, Marissa D. Cortopassi, Shannon Prouty, Bernardo L. Sabatini","doi":"10.1016/j.cell.2024.07.041","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.041","url":null,"abstract":"<p>Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone—a regulator of metabolism in many peripheral organs—directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023035","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 : 2024-08-22DOI: 10.1016/j.cell.2024.07.032
Rohan Palanki, Hannah Yamagata, Michael J. Mitchell
Respiratory virus infections may cause profound respiratory illness, yet the factors that underlie disease severity are not well understood. In this issue of Cell, Jia, Crawford, et al.1 identify the role of oleoyl-ACP-hydrolase (OLAH) in mediating life-threatening inflammation associated with viral respiratory disease severity.
{"title":"OLAH connects fatty acid metabolism to the severity of respiratory viral disease","authors":"Rohan Palanki, Hannah Yamagata, Michael J. Mitchell","doi":"10.1016/j.cell.2024.07.032","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.032","url":null,"abstract":"<p>Respiratory virus infections may cause profound respiratory illness, yet the factors that underlie disease severity are not well understood. In this issue of <em>Cell</em>, Jia, Crawford, et al.<span><span><sup>1</sup></span></span> identify the role of oleoyl-ACP-hydrolase (OLAH) in mediating life-threatening inflammation associated with viral respiratory disease severity.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023055","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 : 2024-08-22DOI: 10.1016/j.cell.2024.07.042
Matthias P. Lutolf, Milica Radisic, Jeffrey Beekman, Dan Dongeun Huh, Meritxell Huch, Margherita Yayoi Turco, Zeinab Niloofar Tahmasebi Birgani, Dong Gao, Rui Yao, Hang Lin, Takanori Takebe
It is said that all models are wrong, but some are useful. In vitro human cell-based models are a prime example of this maxim. We asked researchers: when is your model system useful? How can it be made more useful? What are its limitations?
{"title":"In vitro human cell-based models: What can they do and what are their limitations?","authors":"Matthias P. Lutolf, Milica Radisic, Jeffrey Beekman, Dan Dongeun Huh, Meritxell Huch, Margherita Yayoi Turco, Zeinab Niloofar Tahmasebi Birgani, Dong Gao, Rui Yao, Hang Lin, Takanori Takebe","doi":"10.1016/j.cell.2024.07.042","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.042","url":null,"abstract":"<p>It is said that all models are wrong, but some are useful. <em>In vitro</em> human cell-based models are a prime example of this maxim. We asked researchers: when is your model system useful? How can it be made more useful? What are its limitations?</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023124","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 : 2024-08-22DOI: 10.1016/j.cell.2024.07.046
No Abstract
无摘要
{"title":"The wide-reaching power of technology","authors":"","doi":"10.1016/j.cell.2024.07.046","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.046","url":null,"abstract":"No Abstract","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043069","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 : 2024-08-22Epub Date: 2024-07-05DOI: 10.1016/j.cell.2024.06.011
Abhirami Visvanathan, Olivier Saulnier, Chuan Chen, Parthiv Haldipur, Wilda Orisme, Alberto Delaidelli, Seungmin Shin, Jake Millman, Andrew Bryant, Namal Abeysundara, Xujia Wu, Liam D Hendrikse, Vikas Patil, Zahedeh Bashardanesh, Joseph Golser, Bryn G Livingston, Takuma Nakashima, Yusuke Funakoshi, Winnie Ong, Alexandra Rasnitsyn, Kimberly A Aldinger, Cory M Richman, Randy Van Ommeren, John J Y Lee, Michelle Ly, Maria C Vladoiu, Kaitlin Kharas, Polina Balin, Anders W Erickson, Vernon Fong, Jiao Zhang, Raúl A Suárez, Hao Wang, Ning Huang, Jonelle G Pallota, Tajana Douglas, Joonas Haapasalo, Ferechte Razavi, Evelina Silvestri, Olga Sirbu, Samantha Worme, Michelle M Kameda-Smith, Xiaochong Wu, Craig Daniels, Antony K MichaelRaj, Aparna Bhaduri, Daniel Schramek, Hiromichi Suzuki, Livia Garzia, Nabil Ahmed, Claudia L Kleinman, Lincoln D Stein, Peter Dirks, Christopher Dunham, Nada Jabado, Jeremy N Rich, Wei Li, Poul H Sorensen, Robert J Wechsler-Reya, William A Weiss, Kathleen J Millen, David W Ellison, Dimiter S Dimitrov, Michael D Taylor
We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.
{"title":"Early rhombic lip Protogenin<sup>+ve</sup> stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.","authors":"Abhirami Visvanathan, Olivier Saulnier, Chuan Chen, Parthiv Haldipur, Wilda Orisme, Alberto Delaidelli, Seungmin Shin, Jake Millman, Andrew Bryant, Namal Abeysundara, Xujia Wu, Liam D Hendrikse, Vikas Patil, Zahedeh Bashardanesh, Joseph Golser, Bryn G Livingston, Takuma Nakashima, Yusuke Funakoshi, Winnie Ong, Alexandra Rasnitsyn, Kimberly A Aldinger, Cory M Richman, Randy Van Ommeren, John J Y Lee, Michelle Ly, Maria C Vladoiu, Kaitlin Kharas, Polina Balin, Anders W Erickson, Vernon Fong, Jiao Zhang, Raúl A Suárez, Hao Wang, Ning Huang, Jonelle G Pallota, Tajana Douglas, Joonas Haapasalo, Ferechte Razavi, Evelina Silvestri, Olga Sirbu, Samantha Worme, Michelle M Kameda-Smith, Xiaochong Wu, Craig Daniels, Antony K MichaelRaj, Aparna Bhaduri, Daniel Schramek, Hiromichi Suzuki, Livia Garzia, Nabil Ahmed, Claudia L Kleinman, Lincoln D Stein, Peter Dirks, Christopher Dunham, Nada Jabado, Jeremy N Rich, Wei Li, Poul H Sorensen, Robert J Wechsler-Reya, William A Weiss, Kathleen J Millen, David W Ellison, Dimiter S Dimitrov, Michael D Taylor","doi":"10.1016/j.cell.2024.06.011","DOIUrl":"10.1016/j.cell.2024.06.011","url":null,"abstract":"<p><p>We identify a population of Protogenin-positive (PRTG<sup>+ve</sup>) MYC<sup>high</sup> NESTIN<sup>low</sup> stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL<sup>VZ</sup>). Oncogenic transformation of early Prtg<sup>+ve</sup> rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG<sup>+ve</sup> stem cells grow adjacent to a human-specific interposed vascular plexus in the RL<sup>VZ</sup>, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTG<sup>high</sup> compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RL<sup>VZ</sup> PRTG<sup>+ve</sup> stem cells inhabiting a specific perivascular niche. Targeting the PRTG<sup>high</sup> compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":45.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544557","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}