Federico Rossari, Giorgia Alvisi, Melania Cusimano, Stefano Beretta, Filippo Birocchi, Deborah I. Ambrosecchia, Ottavia Vitaloni, Chiara Brombin, Paola Maria Vittoria Rancoita, Tamara Canu, Giorgio Orofino, Andrea Annoni, Bernhard Gentner, Mario Leonardo Squadrito, Marco Genua, Renato Ostuni, Ivan Merelli, Nadia Coltella, Luigi Naldini
{"title":"A cross-talk established by tumor-targeted cytokines rescues CAR T cell activity and engages host T cells against glioblastoma in mice","authors":"Federico Rossari, Giorgia Alvisi, Melania Cusimano, Stefano Beretta, Filippo Birocchi, Deborah I. Ambrosecchia, Ottavia Vitaloni, Chiara Brombin, Paola Maria Vittoria Rancoita, Tamara Canu, Giorgio Orofino, Andrea Annoni, Bernhard Gentner, Mario Leonardo Squadrito, Marco Genua, Renato Ostuni, Ivan Merelli, Nadia Coltella, Luigi Naldini","doi":"10.1126/scitranslmed.ado9511","DOIUrl":"10.1126/scitranslmed.ado9511","url":null,"abstract":"<div >Chimeric antigen receptor (CAR) T cells have shown limited efficacy against solid tumors because of poor tissue penetration, constrained activity, and early exhaustion due to the immunosuppressive tumor microenvironment (TME). Although stimulatory cytokines can counteract immune suppression, their systemic administration entails risk of toxicities and counter-regulatory responses. Here, we leveraged a population of tumor-associated TIE2-expressing macrophages (TEMs) to release interferon-α (IFN-α) and/or orthogonal interleukin-2 (oIL2) at the tumor site. Targeted cytokine delivery rescued CAR T cell functionality against the clinically relevant tumor antigen B7-homolog 3 (B7-H3) in an orthotopic, CAR T cell–refractory, immunocompetent mouse model of glioblastoma (GBM) named mGB2 that recapitulates pathological features of the human disease. Immunophenotypic and transcriptomic analyses revealed that inhibition of premature terminal exhaustion and induction of effector and memory states featuring activation of signaling pathways and transcriptional networks putatively boosted CAR T cell antitumor activity. Furthermore, IFN-α, especially when combined with private oIL2 signaling to CAR T cells, elicited potent endogenous T cell responses against multiple tumor-associated antigens, leading to delayed GBM growth and prolonged mouse survival even with tumors expressing B7-H3 in only a fraction of cells. These data suggest that the combination of TEM-based cytokine delivery and CAR T cells may have synergistic effects and support the further study of this approach for the treatment of patients with GBM.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 805","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chrissy Bolton, Christopher B. Mahony, Elizabeth Clay, Patricia Reis Nisa, Søren Lomholt, Annie Hackland, Paulynn S. Chin, Charlotte G. Smith, Vicky Alexiou, Huong D. Nguyen, Manigandan Thyagarajan, Zishan Sheikh, Penny Davis, Samantha Chippington, Sandrine Compeyrot-Lacassagne, Sunit Davda, Charlene Foley, Inga Turtsevich, Benjamin Ingledow, Klaudia Kupiec, James Kelly, Megan M. Hanlon, Edward DiCarlo, Luke J. Jones, Samantha L. Smith, Stephen Eyre, Georgiana Neag, Samuel Kemble, Roopa Madhu, Mukta G. Palshikar, Ilya Korsunsky, Ce Gao, Miles Tran, Calliope Dendrou, Christopher D. Buckley, Mark C. Coles, Karim Raza, the MAPJAG Study Group, Ellen Gravallese, Andrew Filer, Kevin Wei, Eslam Al-Abadi, Elizabeth C. Rosser, Lucy R. Wedderburn, Adam P. Croft
{"title":"Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity","authors":"Chrissy Bolton, Christopher B. Mahony, Elizabeth Clay, Patricia Reis Nisa, Søren Lomholt, Annie Hackland, Paulynn S. Chin, Charlotte G. Smith, Vicky Alexiou, Huong D. Nguyen, Manigandan Thyagarajan, Zishan Sheikh, Penny Davis, Samantha Chippington, Sandrine Compeyrot-Lacassagne, Sunit Davda, Charlene Foley, Inga Turtsevich, Benjamin Ingledow, Klaudia Kupiec, James Kelly, Megan M. Hanlon, Edward DiCarlo, Luke J. Jones, Samantha L. Smith, Stephen Eyre, Georgiana Neag, Samuel Kemble, Roopa Madhu, Mukta G. Palshikar, Ilya Korsunsky, Ce Gao, Miles Tran, Calliope Dendrou, Christopher D. Buckley, Mark C. Coles, Karim Raza, the MAPJAG Study Group, Ellen Gravallese, Andrew Filer, Kevin Wei, Eslam Al-Abadi, Elizabeth C. Rosser, Lucy R. Wedderburn, Adam P. Croft","doi":"10.1126/scitranslmed.adt6050","DOIUrl":"10.1126/scitranslmed.adt6050","url":null,"abstract":"<div >Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident <i>SPP1<sup>+</sup></i> macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β–responsive stromal subsets that up-regulate expression of disease risk–associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 805","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kohji Kato, Yosuke Nishio, Kirsty J. McMillan, Aljazi Al-Maraghi, Hester Y. Kroes, Mohamed S. Abdel-Hamid, Emma Jones, Shrestha Shaw, Aya Yoshida, Shiomi Otsuji, Yuka Murofushi, Waleed Aamer, Ajaz A. Bhat, Jehan AlRayahi, Ammira S. Al-Shabeeb Akil, Elbay Aliyev, Ellen van Binsbergen, Etienne J. Janssen, Kazi Mahnaz Mehrin, Hisashi Oishi, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Akihiko Saito, Mitsuharu Hattori, Yoshihiko Kawano, Philip A. Lewis, Kate J. Heesom, Takeshi Takarada, Kazunobu Sawamoto, Masaki Matsushita, Tomoo Ogi, Rebeka Butkovic, Chris Danson, Kevin A. Wilkinson, Khalid A. Fakhro, Maha S. Zaki, Shinji Saitoh, Peter J. Cullen
{"title":"Ritscher-Schinzel syndrome can be characterized as an endosomal recyclinopathy","authors":"Kohji Kato, Yosuke Nishio, Kirsty J. McMillan, Aljazi Al-Maraghi, Hester Y. Kroes, Mohamed S. Abdel-Hamid, Emma Jones, Shrestha Shaw, Aya Yoshida, Shiomi Otsuji, Yuka Murofushi, Waleed Aamer, Ajaz A. Bhat, Jehan AlRayahi, Ammira S. Al-Shabeeb Akil, Elbay Aliyev, Ellen van Binsbergen, Etienne J. Janssen, Kazi Mahnaz Mehrin, Hisashi Oishi, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Akihiko Saito, Mitsuharu Hattori, Yoshihiko Kawano, Philip A. Lewis, Kate J. Heesom, Takeshi Takarada, Kazunobu Sawamoto, Masaki Matsushita, Tomoo Ogi, Rebeka Butkovic, Chris Danson, Kevin A. Wilkinson, Khalid A. Fakhro, Maha S. Zaki, Shinji Saitoh, Peter J. Cullen","doi":"10.1126/scitranslmed.adt2426","DOIUrl":"10.1126/scitranslmed.adt2426","url":null,"abstract":"<div >Ritscher-Schinzel syndrome (RSS) is a congenital malformation syndrome characterized by cerebellar, cardiac, and craniofacial malformations and phenotypes associated with liver, skeletal, and kidney dysfunction. The genetic cause of RSS remains to be fully defined, and limited information is available regarding the root cause of the multiple tissue phenotypes. Causative mutations in the Commander multiprotein assembly are an emerging feature of this syndrome. Commander organizes the sorting nexin-17 (SNX17)–dependent recycling of hundreds of integral membrane proteins through the endosomal network. Here, we identify previously unrecognized cohorts of patients with RSS that we genetically and clinically analyzed to identify causative genes in the copper metabolic murr1 domain–containing (COMMD) proteins COMMD4, COMMD9, and coiled-coil domain containing 93 (CCDC93) subunits of the Commander complex. Using interactome analysis, we determined that these mutations disrupted Commander assembly and, through cell surface proteomics, that this reduces tissue-specific presentation of cell surface integral membrane proteins essential for kidney, bone, and brain development. We established that these integral proteins contained ΦxNPxY/F or ΦxNxxY/F sorting motifs in their cytoplasmic-facing domains (where Φ is a hydrophobic residue and x is any residue) that are recognized by SNX17 to drive their Commander-dependent endosomal recycling. Last, through generation of mouse models of RSS, we show replication of RSS-associated clinical phenotypes including proteinuria, skeletal malformation, and neurological impairment. Our data establish RSS as a “recyclinopathy” that arises from a dysfunction in the Commander endosomal recycling pathway.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 805","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Bile diversion underlies Roux-en-Y antitumor benefits","authors":"Elizabeth R. M. Zunica, Vance L. Albaugh","doi":"10.1126/scitranslmed.adx3814","DOIUrl":"10.1126/scitranslmed.adx3814","url":null,"abstract":"<div >Bile diversion in preclinical Roux-en-Y gastric bypass confers its antitumor effects independently of weight loss (Lässle <i>et al.</i>, this issue).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 804","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Romain Guyon, Sören Reinke, Adam Truby, Lee Sims, Adrian V. S. Hill, Luca Bau, Eleanor Stride, Anita Milicic
{"title":"Core-shell microcapsules compatible with routine injection enable prime/boost immunization against malaria with a single shot","authors":"Romain Guyon, Sören Reinke, Adam Truby, Lee Sims, Adrian V. S. Hill, Luca Bau, Eleanor Stride, Anita Milicic","doi":"10.1126/scitranslmed.adw2256","DOIUrl":"10.1126/scitranslmed.adw2256","url":null,"abstract":"<div >Inadequate booster uptake threatens the success of immunization campaigns as seen with the recently rolled-out R21 malaria vaccine. The ability to administer both prime and boost immunizations with a single injection would therefore save lives and alleviate health care burdens. We present a platform for delayed delivery of the booster dose that is scalable with existing technology, easily injectable, and protective against malaria in vivo. Using chip-based microfluidics, we encapsulated the R21 malaria vaccine in polymer microcapsules that release their content weeks to months postinjection. Coinjecting microcapsules with the priming dose of the R21 vaccine elicited strong antibody responses in a mouse model and provided 85% of the protection of a standard prime/boost schedule. If confirmed in humans, these results would pave the way for rapid deployment of single-shot prime/boost vaccination, an urgently needed global health intervention.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 804","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lisa Turinsky, Sonja Rehrl, Clément Nguyen, Siham Benyahia, Nicolas Kuperwasser, Florence Vasseur, Alis Restrepo Arevalo, Marion Rabant, Nicolas Goudin, Laurent Mesnard, Guillaume Canaud, Marco Pontoglio, Pierre Isnard, Fabiola Terzi
{"title":"Podocyte-specific YAP activation triggers crescentic glomerulonephritis through cross-talk with parietal epithelial cells","authors":"Lisa Turinsky, Sonja Rehrl, Clément Nguyen, Siham Benyahia, Nicolas Kuperwasser, Florence Vasseur, Alis Restrepo Arevalo, Marion Rabant, Nicolas Goudin, Laurent Mesnard, Guillaume Canaud, Marco Pontoglio, Pierre Isnard, Fabiola Terzi","doi":"10.1126/scitranslmed.adq7825","DOIUrl":"10.1126/scitranslmed.adq7825","url":null,"abstract":"<div >Crescentic glomerulonephritis (cGN) is a severe kidney pathology characterized by the aberrant proliferation of epithelial cells, leading to crescent formation within the Bowman’s space. The molecular pathways involved in crescent formation remain poorly understood despite its clinical relevance. Given the mechanical stress experienced by podocytes, likely exacerbated in cGN, we hypothesized that activation of the mechanosensor yes-associated protein 1 (YAP), an effector of the Hippo pathway, may contribute to the development of cGN. Here, we demonstrate activation of YAP and its target genes in the nephrotoxic nephritis model, a murine model of cGN. Mechanistically, podocyte-specific hyperactivation of YAP (YAP<sup>5SA</sup>) in transgenic mice led to cell-autonomous hypertrophy of podocytes and non–cell-autonomous activation and proliferation of parietal epithelial cells (PECs), culminating in crescents. Transcriptomic profiling in a human podocyte cell line expressing the same YAP<sup>5SA</sup> isoform revealed the reactivation of developmental programs within differentiated podocytes and identified the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin (PI3K-Akt-mTOR) signaling pathway as a candidate involved in YAP-induced podocyte hypertrophy. Furthermore, this analysis identified connective tissue growth factor (CTGF) and heparin-binding epidermal growth factor–like growth factor (HB-EGF) as potential mediators in the cross-talk between YAP-activated podocytes and PECs, driving PEC hyperplasia. Collectively, these findings highlight the pivotal role of YAP in the pathogenesis of cGN and indicate that targeting YAP signaling could be a promising therapeutic strategy for this severe kidney disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 804","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A cationic polymer drives glycosaminoglycan assembly and secretion for preclinical osteoarthritis therapy","authors":"Yishan Chen, Wei Sun, Ya Wen, Xiaozhao Wang, Jiachen Li, Shaofang Xie, Rui Li, Yuanzhu Ma, Hongwei Wu, Qiuwen Zhu, Ziheng Chen, Xianzhu Zhang, Youguo Liao, Junxin Lin, Wenyue Li, Yiyang Yan, Dingchao Ying, Qiulin He, Hongxu Meng, Chong Teng, Wenyan Zhou, Yong Wang, Xu Li, Zi Yin, Wei Wei, Kam W. Leong, Hongwei Ouyang","doi":"10.1126/scitranslmed.adl5623","DOIUrl":"10.1126/scitranslmed.adl5623","url":null,"abstract":"<div >Osteoarthritis (OA) affects nearly 500 million people worldwide and is characterized by an irreversible loss of glycosaminoglycans (GAGs) at articular cartilage surfaces, which are essential in maintaining cartilage mechanical properties and chondrocyte phenotypes. Despite advances, preserving cartilage GAGs and controlling their turnover in living cells remain challenging. On the basis of the hypothesis that GAGs can interact with cationic molecules, we demonstrated a cost-effective strategy to increase human cartilage GAGs using a cationic polymer hexadimethrine bromide (HDMBr). HDMBr promoted chondrogenesis of mesenchymal stem cells by attracting pericellular GAGs and up-regulating vesicle formation, leading to increased matrix secretion. HDMBr also acted like a molecular assembler to promote the assembly of chondroitin sulfate (CS) into highly concentrated condensates during intracellular trafficking, resulting in more efficient GAG secretion. HDMBr was then evaluated as a potential therapeutic in two animal models. In a rabbit model of large cartilage defects, HDMBr promoted the intrinsic regeneration of GAG-rich hyaline-like cartilage and improved tissue integration. In a rat model of OA, low-dose HDMBr treatment increased cartilage thickness, supported cartilage matrix homeostasis, and supported cell-based therapy, reducing OA damage as compared with other tested clinical treatments. Overall, this study introduces a cost-effective GAG manipulation approach to cartilage repair and joint preservation, offering insights into the mechanisms of cell-material interactions.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 804","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Erratum for the Research Article “ALK is a therapeutic target for lethal sepsis” by L. Zeng et al.","authors":"","doi":"10.1126/scitranslmed.adz3926","DOIUrl":"10.1126/scitranslmed.adz3926","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 804","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Claudia Lässle, Bernhard Mauerer, Lisa Marx, Reinhild Feuerstein, Heidi Braumüller, Veit Broghammer, Luisa Schäfer, Celine Enderle, Jost Lünstedt, Gabriel Seifert, Goran Marjanovic, Ziwen Zheng, Philipp Holzner, Stefan Fichtner-Feigl, Christopher Berlin, Rebecca Kesselring
{"title":"Metabolic surgery reduces CRC disease progression through circulating bile acid diversion","authors":"Claudia Lässle, Bernhard Mauerer, Lisa Marx, Reinhild Feuerstein, Heidi Braumüller, Veit Broghammer, Luisa Schäfer, Celine Enderle, Jost Lünstedt, Gabriel Seifert, Goran Marjanovic, Ziwen Zheng, Philipp Holzner, Stefan Fichtner-Feigl, Christopher Berlin, Rebecca Kesselring","doi":"10.1126/scitranslmed.ads9705","DOIUrl":"10.1126/scitranslmed.ads9705","url":null,"abstract":"<div >Obesity is a global epidemic characterized by energy disequilibrium, metabolic disorders, and fat mass development that greatly affect the health status of individuals. There is evidence that the intake of a high-fat diet and overweight are associated with the incidence of colorectal cancer (CRC). Metabolic surgery has been associated with improvements in obesity-related comorbidities and a reduction in the overall cancer risk. However, the underlying mechanism by which metabolic surgery reduces the risk of CRC remains unknown. To understand the antitumoral mechanism of bariatric surgery, we analyzed the development of CRC after Roux-en-Y gastric bypass (RYGB) surgery in an RYGB-CRC mouse model. Here, we showed that RYGB surgery substantially reduced primary tumorigenesis and prevented metastasis. This protective effect was mediated by bile acid (BA) exclusion from the proximal small intestine, leading to BA diversion in the preceding parts of the gastrointestinal tract and in circulation. The diverted BA profile in RYGB mice showed antitumoral and antimetastatic effects that were verified by BA exclusion of the proximal small bowel without the systemic metabolic installations of RYGB surgery by a cholecystointestinal shunt (CIS) surgery. RYGB surgery thus leads to reduced primary BAs and elevated secondary BAs in circulation. In a translational study involving patients with CRC with metachronous liver metastases, we confirmed that reduced primary BA concentrations in the serum were associated with prolonged time to metastasis, underscoring the critical role of BAs in CRC progression and metastatic development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 804","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaolin He, Estefania Rodriguez Ballestas, Li Zeng, Tianzhou Zhang, Caitriona M. McEvoy, Paraish S. Misra, Victoria Ki, Arnold Apostol, Jenny S. Wong, Kristin Meliambro, Justina Ray, Marina De Cos, Maria Elena Melica, Paola Romagnani, Ye Feng, Adriana Krizova, Ira How, Ivy A. Rosales, Robert B. Colvin, John Cijiang He, Kirk N. Campbell, Darren A. Yuen
{"title":"Podocyte YAP and TAZ hyperactivation drives glomerular epithelial proliferative diseases in mice and humans","authors":"Xiaolin He, Estefania Rodriguez Ballestas, Li Zeng, Tianzhou Zhang, Caitriona M. McEvoy, Paraish S. Misra, Victoria Ki, Arnold Apostol, Jenny S. Wong, Kristin Meliambro, Justina Ray, Marina De Cos, Maria Elena Melica, Paola Romagnani, Ye Feng, Adriana Krizova, Ira How, Ivy A. Rosales, Robert B. Colvin, John Cijiang He, Kirk N. Campbell, Darren A. Yuen","doi":"10.1126/scitranslmed.adq3852","DOIUrl":"10.1126/scitranslmed.adq3852","url":null,"abstract":"<div >Kidney diseases characterized by glomerular epithelial cell proliferation are rare but often devastating, frequently leading to progressive scarring and renal failure. Ranging from autoimmune-induced crescentic glomerulonephritis to HIV infection–induced collapsing glomerulopathy, these diseases are triggered by a wide variety of insults and have generally been thought of as different entities. Here, using immunostaining and spatial transcriptomics, we profiled human kidney biopsies collected from patients with two of these diseases, collapsing glomerulopathy and antineutrophil cytoplasmic antibody (ANCA) vasculitis-induced crescentic glomerulonephritis, to identify common disease-causing molecules. Although triggered by different insults, we identified abnormal hyperactivation of the transcription cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes as a potential common driver of these diseases. To test this hypothesis, we genetically activated podocyte YAP and TAZ in cultured human cells and in mice by deleting the YAP and TAZ inhibitory large tumor suppressor kinases (LATSs). LATS deficiency in mouse podocytes induced a phenotypic transition in vitro, characterized by a highly distorted structure and an increase in matrix gene expression, mimicking many features of the podocytopathy seen in diseases characterized by glomerular epithelial proliferation. In mice, LATS-deficient podocytes orchestrated a profibrotic and pro-proliferative response in surrounding glomerular cells, a characteristic phenomenon of glomerular epithelial proliferative diseases. This response was attenuated when we also deleted podocyte YAP or TAZ in these mice. Together, our findings point to podocyte YAP-TAZ hyperactivation as a previously unrecognized and unifying driver of glomerular epithelial proliferative diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 804","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}