Zhibo Wang, Yuhan Chen, Katherine Gong, Bote Zhao, Yuye Ning, Meilin Chen, Yan Li, Muhammad Ali, Jigyasha Timsina, Menghan Liu, Carlos Cruchaga, Jianping Jia
{"title":"Cerebrospinal fluid proteomics identification of biomarkers for amyloid and tau PET stages.","authors":"Zhibo Wang, Yuhan Chen, Katherine Gong, Bote Zhao, Yuye Ning, Meilin Chen, Yan Li, Muhammad Ali, Jigyasha Timsina, Menghan Liu, Carlos Cruchaga, Jianping Jia","doi":"10.1016/j.xcrm.2025.102031","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102031","url":null,"abstract":"<p><p>Accurate staging of Alzheimer's disease (AD) pathology is crucial for therapeutic trials and prognosis, but existing fluid biomarkers lack specificity, especially for assessing tau deposition severity, in amyloid-beta (Aβ)-positive patients. We analyze cerebrospinal fluid (CSF) samples from 136 participants in the Alzheimer's Disease Neuroimaging Initiative using more than 6,000 proteins. We apply machine learning to predict AD pathological stages defined by amyloid and tau positron emission tomography (PET). We identify two distinct protein panels: 16 proteins, including neurofilament heavy chain (NEFH) and SPARC-related modular calcium-binding protein 1 (SMOC1), that distinguished Aβ-negative/tau-negative (A-T-) from A+ individuals and nine proteins, such as HCLS1-associated protein X-1 (HAX1) and glucose-6-phosphate isomerase (GPI), that differentiated A+T+ from A+T- stages. These signatures outperform the established CSF biomarkers (area under the curve [AUC]: 0.92 versus 0.67-0.70) and accurately predicted disease progression over a decade. The findings are validated in both internal and external cohorts. These results underscore the potential of proteomic-based signatures to refine AD diagnostic criteria and improve patient stratification in clinical trials.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102031"},"PeriodicalIF":11.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673348","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}
Martina Antonini Cencicchio, Federico Montini, Vittoria Palmieri, Luca Massimino, Marta Lo Conte, Annamaria Finardi, Alessandra Mandelli, Francesco Asnicar, Radmila Pavlovic, Denise Drago, Federica Ungaro, Annapaola Andolfo, Nicola Segata, Vittorio Martinelli, Roberto Furlan, Marika Falcone
{"title":"Microbiota-produced immune regulatory bile acid metabolites control central nervous system autoimmunity.","authors":"Martina Antonini Cencicchio, Federico Montini, Vittoria Palmieri, Luca Massimino, Marta Lo Conte, Annamaria Finardi, Alessandra Mandelli, Francesco Asnicar, Radmila Pavlovic, Denise Drago, Federica Ungaro, Annapaola Andolfo, Nicola Segata, Vittorio Martinelli, Roberto Furlan, Marika Falcone","doi":"10.1016/j.xcrm.2025.102028","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102028","url":null,"abstract":"<p><p>The commensal gut microbiota has a role in the pathogenesis of extra-intestinal autoimmune diseases such as multiple sclerosis (MS) with unknown mechanisms. Deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary bile acid metabolites (BAMs) produced from primary bile acids by gut microbiota that play key immune regulatory functions by promoting FOXP3<sup>+</sup> regulatory T (Treg) cell differentiation at the expense of Th17 cells. Here, we show that bacteria releasing enzymes responsible for secondary BAMs production are under-represented in the gut of MS patients, resulting in significantly reduced intestinal concentration of DCA and immune dysregulation with increased percentage of Th17 cells. We validated our human findings in a preclinical model of MS by showing that DCA/LCA administration prevents experimental autoimmune encephalomyelitis (EAE) by dampening Th17 cell differentiation and the effector phenotype of myelin-reactive T cells. Our data highlight the key role of immune regulatory BAMs for the prevention of central nervous system (CNS) autoimmunity.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102028"},"PeriodicalIF":11.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656307","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}
Juanita S Lopez, Mohammed Milhem, Marcus O Butler, Fiona Thistlethwaite, Brian A Van Tine, Sandra P D'Angelo, Melissa L Johnson, Takami Sato, Hendrik-Tobias Arkenau, Ramakrishna Edukulla, Jason Wustner, Shannon Marshall, Jordi Rodon
{"title":"Phase 1 study of IMCnyeso, a T cell receptor bispecific ImmTAC targeting NY-ESO-1-expressing malignancies.","authors":"Juanita S Lopez, Mohammed Milhem, Marcus O Butler, Fiona Thistlethwaite, Brian A Van Tine, Sandra P D'Angelo, Melissa L Johnson, Takami Sato, Hendrik-Tobias Arkenau, Ramakrishna Edukulla, Jason Wustner, Shannon Marshall, Jordi Rodon","doi":"10.1016/j.xcrm.2025.101994","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101994","url":null,"abstract":"<p><p>IMCnyeso, an immune mobilizing monoclonal T cell receptor against cancer (ImmTAC) bispecific (New York esophageal squamous cell carcinoma [NY-ESO]×CD3) T cell engager, targets an NY-ESO-1/L-antigen family member-1 isoform A (LAGE-1A) peptide presented by histocompatibility leukocyte antigen (HLA)-A∗02:01. In this phase 1 study, 28 HLA-A∗02:01+ patients with advanced NY-ESO-1/LAGE-1A-positive advanced tumors (n = 28) receive IMCnyeso weekly intravenously (dose range: 3-300 μg; 7 dose-escalation cohorts). The primary objective is to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D); additional objectives include preliminary anti-tumor activity, pharmacokinetics, immunogenicity, and pharmacodynamic changes. The study was terminated before fully enrolling dose escalation, and the MTD was not identified. There are no treatment-related discontinuations or deaths. The most common adverse events are grade 1/2 cytokine release syndrome and associated symptoms. Cytokine induction and transient lymphocyte count decreases are observed at doses 30-300 μg. At these doses, preliminary efficacy includes mixed response (2 patients) and a median overall survival of 12 months. IMCnyeso is well tolerated and, at doses ≥30 μg, induces pharmacodynamic changes consistent with T cell redirection. This study was registered at ClinicalTrials.gov (NCT03515551).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101994"},"PeriodicalIF":11.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584937","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}
Xuexin Li, Lu Pan, Weiyuan Li, Bingyang Liu, Chunjie Xiao, Valerie Chew, Xuan Zhang, Wang Long, Florent Ginhoux, Joseph Loscalzo, Marcus Buggert, Xiaolu Zhang, Ren Sheng, Zhenning Wang
{"title":"Deciphering immune predictors of immunotherapy response: A multiomics approach at the pan-cancer level.","authors":"Xuexin Li, Lu Pan, Weiyuan Li, Bingyang Liu, Chunjie Xiao, Valerie Chew, Xuan Zhang, Wang Long, Florent Ginhoux, Joseph Loscalzo, Marcus Buggert, Xiaolu Zhang, Ren Sheng, Zhenning Wang","doi":"10.1016/j.xcrm.2025.101992","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101992","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) therapy has transformed cancer treatment, yet many patients fail to respond. Employing single-cell multiomics, we unveil T cell dynamics influencing ICB response across 480 pan-cancer and 27 normal tissue samples. We identify four immunotherapy response-associated T cells (IRATs) linked to responsiveness or resistance and analyze their pseudotemporal patterns, regulatory mechanisms, and T cell receptor clonal expansion profiles specific to each response. Notably, transforming growth factor β1 (TGF-β1)+ CD4<sup>+</sup> and Temra CD8<sup>+</sup> T cells negatively correlate with therapy response, in stark contrast to the positive response associated with CXCL13+ CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Validation with a cohort of 23 colorectal cancer (CRC) samples confirms the significant impact of TGF-β1+ CD4<sup>+</sup> and CXCL13+ CD4<sup>+</sup> and CD8<sup>+</sup> T cells on ICB efficacy. Our study highlights the effectiveness of single-cell multiomics in pinpointing immune markers predictive of immunotherapy outcomes, providing an important resource for crafting targeted immunotherapies for successful ICB treatment across cancers.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101992"},"PeriodicalIF":11.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584933","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}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-01-30DOI: 10.1016/j.xcrm.2025.101935
Hong Yang, Dila Atak, Meng Yuan, Mengzhen Li, Ozlem Altay, Elif Demirtas, Ibrahim Batuhan Peltek, Burge Ulukan, Buket Yigit, Tarik Sipahioglu, María Bueno Álvez, Lingqi Meng, Bayram Yüksel, Hasan Turkez, Hale Kirimlioglu, Burcu Saka, Cihan Yurdaydin, Murat Akyildiz, Murat Dayangac, Mathias Uhlen, Jan Boren, Cheng Zhang, Adil Mardinoglu, Mujdat Zeybel
{"title":"Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies.","authors":"Hong Yang, Dila Atak, Meng Yuan, Mengzhen Li, Ozlem Altay, Elif Demirtas, Ibrahim Batuhan Peltek, Burge Ulukan, Buket Yigit, Tarik Sipahioglu, María Bueno Álvez, Lingqi Meng, Bayram Yüksel, Hasan Turkez, Hale Kirimlioglu, Burcu Saka, Cihan Yurdaydin, Murat Akyildiz, Murat Dayangac, Mathias Uhlen, Jan Boren, Cheng Zhang, Adil Mardinoglu, Mujdat Zeybel","doi":"10.1016/j.xcrm.2025.101935","DOIUrl":"10.1016/j.xcrm.2025.101935","url":null,"abstract":"<p><p>Chronic hepatic injury and inflammation from various causes can lead to fibrosis and cirrhosis, potentially predisposing to hepatocellular carcinoma. The molecular mechanisms underlying fibrosis and its progression remain incompletely understood. Using a proteo-transcriptomics approach, we analyze liver and plasma samples from 330 individuals, including 40 healthy individuals and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease. Our findings reveal dysregulated pathways related to extracellular matrix, immune response, inflammation, and metabolism in advanced fibrosis. We also identify 132 circulating proteins associated with advanced fibrosis, with neurofascin and growth differentiation factor 15 demonstrating superior predictive performance for advanced fibrosis(area under the receiver operating characteristic curve [AUROC] 0.89 [95% confidence interval (CI) 0.81-0.97]) compared to the fibrosis-4 model (AUROC 0.85 [95% CI 0.78-0.93]). These findings provide insights into fibrosis pathogenesis and highlight the potential for more accurate non-invasive diagnosis.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101935"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073938","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}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-11DOI: 10.1016/j.xcrm.2025.101947
Ruoqi Liu, Lang Li, Ping Zhang
{"title":"Estimating the treatment effects of multiple drug combinations on multiple outcomes in hypertension.","authors":"Ruoqi Liu, Lang Li, Ping Zhang","doi":"10.1016/j.xcrm.2025.101947","DOIUrl":"10.1016/j.xcrm.2025.101947","url":null,"abstract":"<p><p>Hypertension management is complex due to the need for multiple drug combinations and consideration of diverse outcomes. Traditional treatment effect estimation methods struggle to address this complexity, as they typically focus on binary treatments and binary outcomes. To overcome these challenges, we introduce a framework that accommodates multiple drug combinations and multiple outcomes (METO). METO uses multi-treatment encoding to handle drug combinations and sequences, distinguishing between effectiveness and safety outcomes by learning the outcome type during prediction. To mitigate confounding bias, METO employs an inverse probability weighting method for multiple treatments, assigning balance weights based on propensity scores. Evaluated on real-world data, METO achieves significant performance improvements over existing methods, with an average improvement of 6.4% in influence function-based precision of estimating heterogeneous effects. A case study demonstrates METO's ability to identify personalized antihypertensive treatments that optimize efficacy and minimize safety risks, highlighting its potential for improving hypertension treatment strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101947"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406014","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}
{"title":"Vitamin E (300 mg) in the treatment of MASH: A multi-center, randomized, double-blind, placebo-controlled study.","authors":"Yu Song, Wenjing Ni, Minghua Zheng, Huiping Sheng, Jing Wang, Shilong Xie, YongFeng Yang, Xiaoling Chi, Jinjun Chen, Fangping He, Xiaotang Fan, Yuqiang Mi, Jing Zhang, Bingyuan Wang, Lang Bai, Wen Xie, Bihui Zhong, Yee Hui Yeo, Fajuan Rui, Shufei Zang, Jie Li, Junping Shi","doi":"10.1016/j.xcrm.2025.101939","DOIUrl":"10.1016/j.xcrm.2025.101939","url":null,"abstract":"<p><p>The efficacy and safety of a lower dose of vitamin E for metabolic dysfunction-associated steatohepatitis (MASH) treatment are unclear. This multi-center, randomized, double-blind, placebo-controlled study includes 124 non-diabetic participants with biopsy-proven MASH. Participants are randomly assigned to receive oral vitamin E 300 mg or the placebo in a 1:1 ratio. The primary outcome is improvement in hepatic histology. In the modified intention-to-treat population, 29.3% of participants in the vitamin E group achieve the primary outcome compared with 14.1% in the placebo group. Significant improvement in steatosis, lobular inflammation, and fibrosis stages is observed in the vitamin E group. 12 serious adverse events are reported in this trial but are not considered to be related to the treatment. Vitamin E 300 mg daily achieves sound improvements in liver histology in the Chinese population with MASH. This study is registered at ClinicalTrials.gov (NCT02962297).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101939"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457077","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}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-01-27DOI: 10.1016/j.xcrm.2025.101929
Seung Yeon Oh, Sewon Park, Seoyoung Lee, Eun Ji Lee, Tae Ho Kim, Su-Jin Choi, So Young Park, Jae Hwan Kim, Sun Min Lim, Jii Bum Lee, Byoung Chul Cho, Min Hee Hong, Mi Ran Yun
{"title":"The potential of lazertinib and amivantamab combination therapy as a treatment strategy for uncommon EGFR-mutated NSCLC.","authors":"Seung Yeon Oh, Sewon Park, Seoyoung Lee, Eun Ji Lee, Tae Ho Kim, Su-Jin Choi, So Young Park, Jae Hwan Kim, Sun Min Lim, Jii Bum Lee, Byoung Chul Cho, Min Hee Hong, Mi Ran Yun","doi":"10.1016/j.xcrm.2025.101929","DOIUrl":"10.1016/j.xcrm.2025.101929","url":null,"abstract":"<p><p>Uncommon epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) pose therapeutic challenge due to limited response to EGFR tyrosine kinase inhibitors (TKIs). This study presents preclinical evidence and mechanistic insights into the combination of lazertinib, a third-generation EGFR-TKI; and amivantamab, an EGFR-MET bispecific antibody, for treating NSCLC with uncommon EGFR mutations. The lazertinib-amivantamab combination demonstrates significant antitumor activity in patient-derived models with uncommon EGFR mutations either before treatment or after progressing on EGFR-TKIs. Lazertinib enhances the inhibitory capacity of amivantamab by increasing its on-target expression. Notably, the combination surpasses afatinib, a first-line treatment for uncommon EGFR mutations in NSCLC, in terms of in vivo efficacy. Promising clinical activity is also observed in two case studies of patients treated with this combination (NCT04077463). Our findings highlight the potential of the lazertinib-amivantamab combination as a therapeutic strategy for uncommon EGFR mutations, an area of unmet medical need, and support further clinical investigation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101929"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058150","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}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-07DOI: 10.1016/j.xcrm.2025.101943
Jared Almazan, Tursun Turapov, David A Kircher, Karly A Stanley, Katie Culver, A Paulina Medellin, MiKaela N Field, Gennie L Parkman, Howard Colman, Silvia Coma, Jonathan A Pachter, Sheri L Holmen
{"title":"Combined inhibition of focal adhesion kinase and RAF/MEK elicits synergistic inhibition of melanoma growth and reduces metastases.","authors":"Jared Almazan, Tursun Turapov, David A Kircher, Karly A Stanley, Katie Culver, A Paulina Medellin, MiKaela N Field, Gennie L Parkman, Howard Colman, Silvia Coma, Jonathan A Pachter, Sheri L Holmen","doi":"10.1016/j.xcrm.2025.101943","DOIUrl":"10.1016/j.xcrm.2025.101943","url":null,"abstract":"<p><p>This study addresses the urgent need for effective therapies for patients with brain metastases from cutaneous melanoma, a major cause of treatment failure despite recent therapeutic advances. Utilizing mouse models that mimic human melanoma brain metastases, this study investigates the necessity of focal adhesion kinase (FAK) in the development of distant metastases and its potential as a therapeutic target. Pharmacological inhibition of FAK demonstrates significant efficacy in reducing the development of brain metastases in preclinical mouse models. Importantly, the study provides insight into the crosstalk between FAK and mitogen-activated protein kinase (MAPK) pathway signaling and highlights the synergistic effects of combined inhibition of FAK, rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase kinase (MEK) in cutaneous melanoma. These findings provide the rationale for clinical evaluation of the efficacy of the FAK inhibitor defactinib and the RAF/MEK inhibitor avutometinib in patients with brain metastases from cutaneous melanoma.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101943"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373792","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}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-01-23DOI: 10.1016/j.xcrm.2024.101925
Luz Yurany Moreno Rueda, Hua Wang, Keiko Akagi, Minghao Dang, Amishi Vora, Li Qin, Hans C Lee, Krina K Patel, Pei Lin, David E Mery, Fenghuang Zhan, John D Shaughnessy, Qing Yi, Yang Song, Bo Jiang, Maura L Gillison, Sheeba K Thomas, Donna M Weber, Lixia Diao, Jing Wang, Isere Kuiatse, Elisabet E Manasanch, David E Symer, Robert Z Orlowski
{"title":"Single-cell analysis of neoplastic plasma cells identifies myeloma pathobiology mediators and potential targets.","authors":"Luz Yurany Moreno Rueda, Hua Wang, Keiko Akagi, Minghao Dang, Amishi Vora, Li Qin, Hans C Lee, Krina K Patel, Pei Lin, David E Mery, Fenghuang Zhan, John D Shaughnessy, Qing Yi, Yang Song, Bo Jiang, Maura L Gillison, Sheeba K Thomas, Donna M Weber, Lixia Diao, Jing Wang, Isere Kuiatse, Elisabet E Manasanch, David E Symer, Robert Z Orlowski","doi":"10.1016/j.xcrm.2024.101925","DOIUrl":"10.1016/j.xcrm.2024.101925","url":null,"abstract":"<p><p>Multiple myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors and has been studied utilizing approaches focused on CD138<sup>+</sup> cells. By combining single-cell RNA sequencing (scRNA-seq) with scB-cell receptor sequencing (scBCR-seq), we differentiate monoclonal/neoplastic from polyclonal/normal PCs and find more dysregulated genes, especially in precursor patients, than we would have by analyzing bulk PCs. To determine whether this approach can identify oncogenes that contribute to disease pathobiology, mitotic arrest deficient-2 like-1 (MAD2L1) and S-adenosylmethionine synthase isoform type-2 (MAT2A) are validated as targets with drug-like molecules that suppress myeloma growth in preclinical models. Moreover, functional studies show a role of lysosomal-associated membrane protein family member-5 (LAMP5), which is uniquely expressed in neoplastic PCs, in tumor progression and aggressiveness via interactions with c-MYC. Finally, a monoclonal antibody recognizing cell-surface LAMP5 shows efficacy as an antibody-drug conjugate and in a chimeric antigen receptor-guided T-cell format. These studies provide additional insights into myeloma biology and identify potential targeted therapeutic approaches that can be applied to reverse myeloma progression.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101925"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037336","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}
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