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Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer. 抑制FGF受体可阻断CCDC6-RET重排甲状腺癌对RET抑制的适应性抵抗。
The Tokushima journal of experimental medicine Pub Date : 2022-06-06 Epub Date: 2022-05-05 DOI: 10.1084/jem.20210390
Renuka Raman, Jacques A Villefranc, Timothy M Ullmann, Jessica Thiesmeyer, Viviana Anelli, Jun Yao, James R Hurley, Chantal Pauli, Rohan Bareja, Kenneth Wha Eng, Princesca Dorsaint, David C Wilkes, Shaham Beg, Sarah Kudman, Reid Shaw, Michael Churchill, Adnan Ahmed, Laurel Keefer, Ian Misner, Donna Nichol, Naveen Gumpeni, Theresa Scognamiglio, Mark A Rubin, Carla Grandori, James Patrick Solomon, Wei Song, Juan Miguel Mosquera, Noah Dephoure, Andrea Sboner, Olivier Elemento, Yariv Houvras
{"title":"Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.","authors":"Renuka Raman, Jacques A Villefranc, Timothy M Ullmann, Jessica Thiesmeyer, Viviana Anelli, Jun Yao, James R Hurley, Chantal Pauli, Rohan Bareja, Kenneth Wha Eng, Princesca Dorsaint, David C Wilkes, Shaham Beg, Sarah Kudman, Reid Shaw, Michael Churchill, Adnan Ahmed, Laurel Keefer, Ian Misner, Donna Nichol, Naveen Gumpeni, Theresa Scognamiglio, Mark A Rubin, Carla Grandori, James Patrick Solomon, Wei Song, Juan Miguel Mosquera, Noah Dephoure, Andrea Sboner, Olivier Elemento, Yariv Houvras","doi":"10.1084/jem.20210390","DOIUrl":"10.1084/jem.20210390","url":null,"abstract":"<p><p>Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75805630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Null IFNAR1 and IFNAR2 alleles are surprisingly common in the Pacific and Arctic. 在太平洋和北极地区，IFNAR1 和 IFNAR2 等位基因无效的现象非常普遍。
The Tokushima journal of experimental medicine Pub Date : 2022-06-06 Epub Date: 2022-04-29 DOI: 10.1084/jem.20220491
Isabelle Meyts
{"title":"Null IFNAR1 and IFNAR2 alleles are surprisingly common in the Pacific and Arctic.","authors":"Isabelle Meyts","doi":"10.1084/jem.20220491","DOIUrl":"10.1084/jem.20220491","url":null,"abstract":"<p><p>In this issue of JEM, Bastard et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220028) show that a loss-of-function IFNAR1 allele is common in western Polynesians, while Duncan et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20212427) report that a loss-of-function IFNAR2 allele is common in Inuits. Homozygotes lack type I IFN immunity but are selectively vulnerable to influenza, COVID-19 pneumonia, and complications of live-attenuated viral vaccines.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79874335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hypoxia induces adrenomedullin from lung epithelia, stimulating ILC2 inflammation and immunity. 缺氧诱导肺上皮细胞分泌肾上腺髓质素，刺激 ILC2 发炎和免疫。
The Tokushima journal of experimental medicine Pub Date : 2022-06-06 Epub Date: 2022-05-09 DOI: 10.1084/jem.20211985
Jihye Han, Qingqing Wan, Goo-Young Seo, Kenneth Kim, Sarah El Baghdady, Jee H Lee, Mitchell Kronenberg, Yun-Cai Liu
{"title":"Hypoxia induces adrenomedullin from lung epithelia, stimulating ILC2 inflammation and immunity.","authors":"Jihye Han, Qingqing Wan, Goo-Young Seo, Kenneth Kim, Sarah El Baghdady, Jee H Lee, Mitchell Kronenberg, Yun-Cai Liu","doi":"10.1084/jem.20211985","DOIUrl":"10.1084/jem.20211985","url":null,"abstract":"<p><p>Hypoxia contributes to airway inflammation and remodeling in several lung diseases; however, exactly how hypoxic pulmonary epithelium regulates allergic inflammation remains to be fully characterized. Here, we report that conditional deletion of the E3 ubiquitin ligase VHL in lung epithelial cells resulted in exacerbated type 2 responses accompanied by selective increase of group 2 innate lymphoid cells (ILC2s) at steady state and following inflammation or helminth infection. Ablation of expression of the hypoxia-inducible factor 2α (HIF2α) significantly reversed VHL-mediated ILC2 activation. VHL deficiency in lung epithelial cells caused increased expression of the peptide hormone adrenomedullin (ADM), and our data suggest that HIF2α controls Adm expression. ADM directly promoted ILC2 activation both in vitro and in vivo. Our findings indicate that the hypoxic response mediated by the VHL-HIF2α axis is critical for control of pulmonary type 2 responses by increasing ADM expression in lung epithelia, causing ILC2 activation.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9093746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84546841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CD4+ T helper 2 cells suppress breast cancer by inducing terminal differentiation CD4+ T辅助2细胞通过诱导终末分化抑制乳腺癌
The Tokushima journal of experimental medicine Pub Date : 2022-06-03 DOI: 10.1084/jem.20201963
M. Boieri, A. Malishkevich, R. Guennoun, E. Marchese, Sanne Kroon, Kathryn E Trerice, Mary E. Awad, Jong Ho Park, Sowmya Iyer, J. Kreuzer, W. Haas, M. Rivera, S. Demehri
{"title":"CD4+ T helper 2 cells suppress breast cancer by inducing terminal differentiation","authors":"M. Boieri, A. Malishkevich, R. Guennoun, E. Marchese, Sanne Kroon, Kathryn E Trerice, Mary E. Awad, Jong Ho Park, Sowmya Iyer, J. Kreuzer, W. Haas, M. Rivera, S. Demehri","doi":"10.1084/jem.20201963","DOIUrl":"https://doi.org/10.1084/jem.20201963","url":null,"abstract":"Boieri et al. demonstrate that CD4+ T helper cells directly block breast cancer development by forcing the cancer cells to terminally differentiate.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73481666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 15
Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming 饮食干预通过ctcf介导的转录重编程保持小鼠β细胞功能
The Tokushima journal of experimental medicine Pub Date : 2022-06-02 DOI: 10.1084/jem.20211779
Ruo-Ran Wang, Xinyuan Qiu, Ran Pan, Hongxing Fu, Ziyin Zhang, Qintao Wang, Haide Chen, Qing-Qian Wu, Xiaowen Pan, Yanping Zhou, Pengfei Shan, Shusen Wang, Guoji Guo, Min Zheng, Lingyun Zhu, Z. Meng
{"title":"Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming","authors":"Ruo-Ran Wang, Xinyuan Qiu, Ran Pan, Hongxing Fu, Ziyin Zhang, Qintao Wang, Haide Chen, Qing-Qian Wu, Xiaowen Pan, Yanping Zhou, Pengfei Shan, Shusen Wang, Guoji Guo, Min Zheng, Lingyun Zhu, Z. Meng","doi":"10.1084/jem.20211779","DOIUrl":"https://doi.org/10.1084/jem.20211779","url":null,"abstract":"Wang et al. systematically characterize the dynamic nature of β cell functional and transcriptomic adaptation along the progression of diet-induced obesity and T2D. They also identify CTCF as a key mediator of dietary intervention–induced preservation β cell function via transcriptional reprogramming.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88977023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 12
Lysophosphatidylserines derived from microbiota in Crohn’s disease elicit pathological Th1 response 来自克罗恩病微生物群的溶血磷脂酰丝氨酸引起病理性Th1反应
The Tokushima journal of experimental medicine Pub Date : 2022-05-24 DOI: 10.1084/jem.20211291
Yuriko Otake-Kasamoto, H. Kayama, T. Kishikawa, S. Shinzaki, T. Tashiro, Takahiro Amano, M. Tani, T. Yoshihara, Bo Li, Haruka Tani, Li Liu, Akio Hayashi, D. Okuzaki, D. Motooka, S. Nakamura, Y. Okada, H. Iijima, K. Takeda, T. Takehara
{"title":"Lysophosphatidylserines derived from microbiota in Crohn’s disease elicit pathological Th1 response","authors":"Yuriko Otake-Kasamoto, H. Kayama, T. Kishikawa, S. Shinzaki, T. Tashiro, Takahiro Amano, M. Tani, T. Yoshihara, Bo Li, Haruka Tani, Li Liu, Akio Hayashi, D. Okuzaki, D. Motooka, S. Nakamura, Y. Okada, H. Iijima, K. Takeda, T. Takehara","doi":"10.1084/jem.20211291","DOIUrl":"https://doi.org/10.1084/jem.20211291","url":null,"abstract":"This study shows that Crohn’s disease–associated microbiota generate lysophosphatidylserines that promote Th1 responses by fueling glycolysis. Lysophosphatidylserine-induced aggravation of colitis is prevented by P2y10 deficiency in CD4+ T cells, demonstrating that dysbiotic microbiota-derived LysoPS exacerbates colitis by modulating Th1 cell metabolism.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73506710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 8
Realigning the LIGHT signaling network to control dysregulated inflammation 重新调整光信号网络以控制失调的炎症
The Tokushima journal of experimental medicine Pub Date : 2022-05-23 DOI: 10.1084/jem.20220236
C. Ware, M. Croft, G. Neil
{"title":"Realigning the LIGHT signaling network to control dysregulated inflammation","authors":"C. Ware, M. Croft, G. Neil","doi":"10.1084/jem.20220236","DOIUrl":"https://doi.org/10.1084/jem.20220236","url":null,"abstract":"The cytokine LIGHT (TNFSF14) has emerged as an important modulator of innate and adaptive immune responses. Accumulating basic and clinical evidence points to the dysregulation of the LIGHT network as a disease-driving mechanism and supports the application of target-modifying therapeutics for disease intervention.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89773041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 10
SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly SARS-CoV-2刺突蛋白通过抑制免疫突触组装抑制ctl介导的杀伤
The Tokushima journal of experimental medicine Pub Date : 2022-05-20 DOI: 10.1101/2022.05.20.492764
A. Onnis, Emanuele Andreano, Chiara Cassioli, Elisa Pantano, Valentina Abbiento, G. Marotta, R. Rappuoli, C. Baldari
{"title":"SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly","authors":"A. Onnis, Emanuele Andreano, Chiara Cassioli, Elisa Pantano, Valentina Abbiento, G. Marotta, R. Rappuoli, C. Baldari","doi":"10.1101/2022.05.20.492764","DOIUrl":"https://doi.org/10.1101/2022.05.20.492764","url":null,"abstract":"CTL-mediated killing of virally infected or malignant cells is orchestrated at a specialized intercellular junction, the immune synapse (IS). We hypothesized that SARS-CoV-2 may target IS assembly in CTLs to escape killing. We show that primary human CD8+ T cells strongly upregulate the expression of ACE2, the Spike protein receptor, during differentiation to CTLs. CTL pre-incubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarisation to the IS, resulting in impaired target cell killing. These defects were reversed by anti-Spike antibodies that interfere with ACE2 binding and were reproduced by ACE2 engagement with Angiotensin-II or an anti-ACE2 antibody, but not by the ACE2 product Ang (1-7). These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent the elimination of infected cells. Summary statement We report a new mechanism of immune evasion by SARS-CoV-2 based on direct disabling CTLs to form immune synapses through Spike protein binding to ACE2. This mechanism could contribute to the failure of the immune system to control SARS-CoV-2 infection.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89612763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 5
Interleukin-4 receptor signaling modulates neuronal network activity 白细胞介素-4受体信号传导调节神经网络活动
The Tokushima journal of experimental medicine Pub Date : 2022-05-19 DOI: 10.1084/jem.20211887
Nicholas Hanuscheck, Carine Thalman, M. Domingues, Samantha Schmaul, M. Muthuraman, Florian Hetsch, Manuela Ecker, Heiko Endle, Mohammadsaleh Oshaghi, G. Martino, T. Kuhlmann, K. Bozek, Tim van Beers, S. Bittner, Jakob von Engelhardt, J. Vogt, C. Vogelaar, F. Zipp
{"title":"Interleukin-4 receptor signaling modulates neuronal network activity","authors":"Nicholas Hanuscheck, Carine Thalman, M. Domingues, Samantha Schmaul, M. Muthuraman, Florian Hetsch, Manuela Ecker, Heiko Endle, Mohammadsaleh Oshaghi, G. Martino, T. Kuhlmann, K. Bozek, Tim van Beers, S. Bittner, Jakob von Engelhardt, J. Vogt, C. Vogelaar, F. Zipp","doi":"10.1084/jem.20211887","DOIUrl":"https://doi.org/10.1084/jem.20211887","url":null,"abstract":"Neuroimmune interaction influences essential CNS processes. Hanuscheck et al. report on the expression of interleukin-4 receptor alpha at presynaptic terminals in mouse and the human brain. The modulation of neuronal IL-4R signaling alters the neuronal transcriptome, impacts synaptic transmission, and causes anxiety-related behavior.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73666337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 7
Matrix reboot: IL-17 signals CAFs to create a second tumor T cell checkpoint 基质重启:IL-17信号CAFs创建第二个肿瘤T细胞检查点
The Tokushima journal of experimental medicine Pub Date : 2022-05-18 DOI: 10.1084/jem.20220444
M. McGeachy
{"title":"Matrix reboot: IL-17 signals CAFs to create a second tumor T cell checkpoint","authors":"M. McGeachy","doi":"10.1084/jem.20220444","DOIUrl":"https://doi.org/10.1084/jem.20220444","url":null,"abstract":"IL-17 promotes collagen deposition by cancer-associated fibroblasts and enhances immune exclusion of tumors.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73731252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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