Pub Date : 2024-09-01Epub Date: 2024-08-09DOI: 10.1038/s44321-024-00102-5
Peiyong Guan, Jianfeng Chen, Chengqiang Mo, Tomoya Fukawa, Chao Zhang, Xiuyu Cai, Mei Li, Jing Han Hong, Jason Yongsheng Chan, Cedric Chuan Young Ng, Jing Yi Lee, Suet Far Wong, Wei Liu, Xian Zeng, Peili Wang, Rong Xiao, Vikneswari Rajasegaran, Swe Swe Myint, Abner Ming Sun Lim, Joe Poh Sheng Yeong, Puay Hoon Tan, Choon Kiat Ong, Tao Xu, Yiqing Du, Fan Bai, Xin Yao, Bin Tean Teh, Jing Tan
Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.
{"title":"Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability.","authors":"Peiyong Guan, Jianfeng Chen, Chengqiang Mo, Tomoya Fukawa, Chao Zhang, Xiuyu Cai, Mei Li, Jing Han Hong, Jason Yongsheng Chan, Cedric Chuan Young Ng, Jing Yi Lee, Suet Far Wong, Wei Liu, Xian Zeng, Peili Wang, Rong Xiao, Vikneswari Rajasegaran, Swe Swe Myint, Abner Ming Sun Lim, Joe Poh Sheng Yeong, Puay Hoon Tan, Choon Kiat Ong, Tao Xu, Yiqing Du, Fan Bai, Xin Yao, Bin Tean Teh, Jing Tan","doi":"10.1038/s44321-024-00102-5","DOIUrl":"10.1038/s44321-024-00102-5","url":null,"abstract":"<p><p>Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-05DOI: 10.1038/s44321-024-00101-6
Julia M Sattler, Lukas Keiber, Aiman Abdelrahim, Xinyu Zheng, Martin Jäcklin, Luisa Zechel, Catherine A Moreau, Smilla Steinbrück, Manuel Fischer, Chris J Janse, Angelika Hoffmann, Franziska Hentzschel, Friedrich Frischknecht
Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.
目前正在探索利用疟原虫活体接种疟疾疫苗的方法,即利用减毒的蚊源性孢子虫或减毒的血期寄生虫。这两种方法都将得益于可获得血期繁殖率降低的减毒和无毒寄生虫。在这里,我们筛选了生长缓慢的啮齿类寄生虫 P. berghei 和人类寄生虫 P. falciparum 的基因缺失突变体。此外,我们还测试了伯格希氏疟原虫突变体的无毒性和解决血期感染的能力,同时保留了孢子虫的形成和肝脏感染。以 51 个基因为靶标,产生了 18 个伯格氏疟原虫基因缺失突变体,其中几个突变体可引起轻度感染。两种最弱的突变体的血液阶段感染或孢子虫感染都能被免疫反应清除。对小鼠进行免疫可使其在受到野生型孢子虫挑战后免于发病。六种恶性疟原虫基因缺失突变体中有两种生长速度缓慢。生长缓慢、无毒的恶性疟原虫突变体将成为诱导免疫反应的宝贵工具,有助于开发新的寄生虫减毒疫苗并保护现有疫苗。
{"title":"Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites.","authors":"Julia M Sattler, Lukas Keiber, Aiman Abdelrahim, Xinyu Zheng, Martin Jäcklin, Luisa Zechel, Catherine A Moreau, Smilla Steinbrück, Manuel Fischer, Chris J Janse, Angelika Hoffmann, Franziska Hentzschel, Friedrich Frischknecht","doi":"10.1038/s44321-024-00101-6","DOIUrl":"10.1038/s44321-024-00101-6","url":null,"abstract":"<p><p>Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-20DOI: 10.1038/s44321-024-00115-0
Xinxing Li, Tao Liu, Antonella Bacchiocchi, Mengxing Li, Wen Cheng, Tobias Wittkop, Fernando L Mendez, Yingyu Wang, Paul Tang, Qianqian Yao, Marcus W Bosenberg, Mario Sznol, Qin Yan, Malek Faham, Li Weng, Ruth Halaban, Hai Jin, Zhiqian Hu
While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10-7, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10-6 circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.
{"title":"Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction.","authors":"Xinxing Li, Tao Liu, Antonella Bacchiocchi, Mengxing Li, Wen Cheng, Tobias Wittkop, Fernando L Mendez, Yingyu Wang, Paul Tang, Qianqian Yao, Marcus W Bosenberg, Mario Sznol, Qin Yan, Malek Faham, Li Weng, Ruth Halaban, Hai Jin, Zhiqian Hu","doi":"10.1038/s44321-024-00115-0","DOIUrl":"10.1038/s44321-024-00115-0","url":null,"abstract":"<p><p>While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10<sup>-7</sup>, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10<sup>-6</sup> circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-21DOI: 10.1038/s44321-024-00111-4
Brittni R Walker, Lise-Michelle Theard, Milena Pinto, Monica Rodriguez-Silva, Sandra R Bacman, Carlos T Moraes
Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.
{"title":"Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy.","authors":"Brittni R Walker, Lise-Michelle Theard, Milena Pinto, Monica Rodriguez-Silva, Sandra R Bacman, Carlos T Moraes","doi":"10.1038/s44321-024-00111-4","DOIUrl":"10.1038/s44321-024-00111-4","url":null,"abstract":"<p><p>Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-26DOI: 10.1038/s44321-024-00104-3
Matthew Hunt, Nuoqi Wang, Naricha Pupinyo, Philip Curman, Monica Torres, William Jebril, Maria Chatzinikolaou, Julie Lorent, Gilad Silberberg, Ritu Bansal, Teresa Burner, Jing Zhou, Susanne Kimeswenger, Wolfram Hoetzenecker, Keith Choate, Etty Bachar-Wikstrom, Jakob D Wikstrom
Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.
达里尔病(Darier disease,DD)是一种罕见的严重棘层溶解性皮肤病,由编码肌浆/内质网钙ATP酶同工酶2(SERCA2)的ATP2A2基因突变引起。SERCA2 通过将钙泵入内质网维持内质网钙平衡,对调节细胞钙动力学和细胞功能至关重要。迄今为止,还没有专门针对 DD 疾病机制的治疗方法。丹曲林钠(Dl)是一种雷诺丁受体拮抗剂,可抑制ER的钙释放,从而提高ER的钙水平,目前用于非皮肤病适应症。在这项研究中,我们首先确定了 DD 患者皮肤中失调的基因和分子通路,显示了细胞粘附和钙平衡通路的下调,以及 ER 应激和细胞凋亡的上调。然后,我们在各种体外 DD 模型和 SERCA2 抑制模型中表明,Dl 有助于保留 ER 钙并促进细胞粘附。此外,Dl 处理可降低 ER 压力并抑制细胞凋亡。我们的研究结果表明,Dl 能特异性地针对 DD 的致病机制,可能是一种潜在的治疗方法。
{"title":"Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment.","authors":"Matthew Hunt, Nuoqi Wang, Naricha Pupinyo, Philip Curman, Monica Torres, William Jebril, Maria Chatzinikolaou, Julie Lorent, Gilad Silberberg, Ritu Bansal, Teresa Burner, Jing Zhou, Susanne Kimeswenger, Wolfram Hoetzenecker, Keith Choate, Etty Bachar-Wikstrom, Jakob D Wikstrom","doi":"10.1038/s44321-024-00104-3","DOIUrl":"10.1038/s44321-024-00104-3","url":null,"abstract":"<p><p>Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-30DOI: 10.1038/s44321-024-00107-0
Marco Losa, Marc Emmenegger, Pierre De Rossi, Patrick M Schürch, Tetiana Serdiuk, Niccolò Pengo, Danaëlle Capron, Dimitri Bieli, Niklas Bargenda, Niels J Rupp, Manfredi C Carta, Karl J Frontzek, Veronika Lysenko, Regina R Reimann, Petra Schwarz, Mario Nuvolone, Gunilla T Westermark, K Peter R Nilsson, Magdalini Polymenidou, Alexandre Pa Theocharides, Simone Hornemann, Paola Picotti, Adriano Aguzzi
Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard-/- mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.
细胞外释放的分子炎症小体集合体--ASC斑点--在阿尔茨海默病中交叉播散Aβ淀粉样蛋白。这是一种在慢性炎症条件下由急性期反应物血清淀粉样蛋白 A(SAA)的聚集和外周沉积引起的全身性疾病。我们利用超分辨率显微镜发现,在人类 AA 淀粉样变性中,ASC 与 SAA 紧密共聚焦。重组 ASC斑点加速了SAA纤维的形成,有限蛋白水解后的质谱分析表明,ASC通过其吡啶结构域(PYD)与SAA相互作用。在炎症性 AA 淀粉样变性小鼠模型中,缺乏 ASC 的 Pycard-/- 小鼠脾脏淀粉样蛋白负荷明显减少。用抗ASCPYD抗体治疗可减少AA淀粉样变性野生型小鼠的淀粉样蛋白负荷。在19334名医院患者中,天然抗ASC IgG(-logEC50 ≥ 2)的流行率为
{"title":"The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis.","authors":"Marco Losa, Marc Emmenegger, Pierre De Rossi, Patrick M Schürch, Tetiana Serdiuk, Niccolò Pengo, Danaëlle Capron, Dimitri Bieli, Niklas Bargenda, Niels J Rupp, Manfredi C Carta, Karl J Frontzek, Veronika Lysenko, Regina R Reimann, Petra Schwarz, Mario Nuvolone, Gunilla T Westermark, K Peter R Nilsson, Magdalini Polymenidou, Alexandre Pa Theocharides, Simone Hornemann, Paola Picotti, Adriano Aguzzi","doi":"10.1038/s44321-024-00107-0","DOIUrl":"10.1038/s44321-024-00107-0","url":null,"abstract":"<p><p>Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard<sup>-/-</sup> mice which lack ASC. Treatment with anti-ASC<sup>PYD</sup> antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC<sub>50</sub> ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-05DOI: 10.1038/s44321-024-00105-2
Jinhai Deng, Teng Pan, Dan Wang, Yourae Hong, Zaoqu Liu, Xingang Zhou, Zhengwen An, Lifeng Li, Giovanna Alfano, Gang Li, Luigi Dolcetti, Rachel Evans, Jose M Vicencio, Petra Vlckova, Yue Chen, James Monypenny, Camila Araujo De Carvalho Gomes, Gregory Weitsman, Kenrick Ng, Caitlin McCarthy, Xiaoping Yang, Zedong Hu, Joanna C Porter, Christopher J Tape, Mingzhu Yin, Fengxiang Wei, Manuel Rodriguez-Justo, Jin Zhang, Sabine Tejpar, Richard Beatson, Tony Ng
Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.
化疗是晚期癌症患者的标准治疗方法,越来越多的人认识到化疗能激活宿主免疫反应,从而产生持久的疗效。在这里,我们在结直肠腺癌(CRC)中发现了奥沙利铂诱导的硫氧还蛋白相互作用蛋白(TXNIP),这是一种依赖于蒙多A的肿瘤抑制基因,是生长/分化因子15(GDF15)的负调控因子。GDF15 是 CRC 的负预后因子,能促进调节性 T 细胞(Tregs)的分化,从而抑制 CD8 T 细胞的活化。耐人寻味的是,包括患者衍生肿瘤器官组织在内的多种模型表明,TXNIP 和 GDF15 对奥沙利铂反应性的丧失与疾病晚期或化疗耐药有关,转录组或蛋白质组 GDF15/TXNIP 比率显示出作为预后生物标志物的潜力。这些发现说明了化疗诱导的上皮氧化应激驱动局部免疫重塑使患者获益的潜在共同途径,在难治或晚期病例中会出现这种途径的破坏。
{"title":"The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas.","authors":"Jinhai Deng, Teng Pan, Dan Wang, Yourae Hong, Zaoqu Liu, Xingang Zhou, Zhengwen An, Lifeng Li, Giovanna Alfano, Gang Li, Luigi Dolcetti, Rachel Evans, Jose M Vicencio, Petra Vlckova, Yue Chen, James Monypenny, Camila Araujo De Carvalho Gomes, Gregory Weitsman, Kenrick Ng, Caitlin McCarthy, Xiaoping Yang, Zedong Hu, Joanna C Porter, Christopher J Tape, Mingzhu Yin, Fengxiang Wei, Manuel Rodriguez-Justo, Jin Zhang, Sabine Tejpar, Richard Beatson, Tony Ng","doi":"10.1038/s44321-024-00105-2","DOIUrl":"10.1038/s44321-024-00105-2","url":null,"abstract":"<p><p>Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-20DOI: 10.1038/s44321-024-00120-3
Yue Wang, Hanbing Wang, Tao Shi, Xueru Song, Xin Zhang, Yue Zhang, Xuan Wang, Keying Che, Yuting Luo, Lixia Yu, Baorui Liu, Jia Wei
The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.
CLDN18-ARHGAP融合基因是胃癌中新发现的致癌驱动基因。本中心在9%(8/87)的胃癌患者中检测到了该基因。我们生成了一种特异性靶向 CLDN18-ARHGAP 融合基因的免疫原性多肽来诱导新抗原反应性 T 细胞,在体外细胞培养模型和体内异种移植胃癌模型中均被证明具有特异性和强大的抗肿瘤能力。除了免疫原性潜力外,研究还发现CLDN18-ARHGAP融合基因还能通过诱导调节性T(Treg)细胞富集的微环境来促进免疫抑制。从机制上讲,CLDN18-ARHGAP融合基因的胃癌细胞会激活PI3K/AKT-mTOR-FAS信号转导,从而增强胃癌细胞的游离脂肪酸生成,有利于Treg细胞的存活。此外,抑制 PI3K 可有效逆转 Treg 细胞的上调,从而增强体外新抗原反应 T 细胞的抗肿瘤细胞毒性,并降低异种移植胃癌模型中的肿瘤生长。我们的研究发现,CLDN18-ARHGAP融合基因是免疫原性新表位的重要来源,是肿瘤免疫微环境的关键调节因子,以及针对这种致癌融合基因的免疫治疗应用。
{"title":"Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer.","authors":"Yue Wang, Hanbing Wang, Tao Shi, Xueru Song, Xin Zhang, Yue Zhang, Xuan Wang, Keying Che, Yuting Luo, Lixia Yu, Baorui Liu, Jia Wei","doi":"10.1038/s44321-024-00120-3","DOIUrl":"10.1038/s44321-024-00120-3","url":null,"abstract":"<p><p>The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target.
{"title":"DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells.","authors":"Jeremy Rich, Melanie Bennaroch, Laura Notel, Polina Patalakh, Julien Alberola, Fayez Issa, Paule Opolon, Olivia Bawa, Windy Rondof, Antonin Marchais, Philippe Dessen, Guillaume Meurice, Morgane Le-Gall, Melanie Polrot, Karine Ser-Le Roux, Kamel Mamchaoui, Nathalie Droin, Hana Raslova, Pascal Maire, Birgit Geoerger, Iryna Pirozhkova","doi":"10.1038/s44321-024-00097-z","DOIUrl":"10.1038/s44321-024-00097-z","url":null,"abstract":"<p><p>We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}