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":"","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":"","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":"","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":"","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":"https://doi.org/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":"","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":"","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":"","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":"","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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-01-28DOI: 10.1016/j.xcrm.2025.101932
Chengbin Ding, Guofeng Tang, Yan Sun, Xiaodong Fu, Ye Tian, Jiamian Zhan, Songtao Zhang, Xianglong Xing, Jianing Liu, Xiaozhong Qiu, Leyu Wang
{"title":"A functional cardiac patch promotes cardiac repair by modulating the CCR2<sup>-</sup> cardiac-resident macrophage niche and their cell crosstalk.","authors":"Chengbin Ding, Guofeng Tang, Yan Sun, Xiaodong Fu, Ye Tian, Jiamian Zhan, Songtao Zhang, Xianglong Xing, Jianing Liu, Xiaozhong Qiu, Leyu Wang","doi":"10.1016/j.xcrm.2025.101932","DOIUrl":"10.1016/j.xcrm.2025.101932","url":null,"abstract":"<p><p>C-C chemokine receptor type 2 (CCR2<sup>-</sup>) cardiac-resident macrophages (CCR2<sup>-</sup> cRMs) are known to promote cardiac repair after myocardial infarction (MI). However, the substantial depletion and slow recovery of CCR2<sup>-</sup> cRMs pose significant barriers in cardiac recovery. Here, we construct a functional conductive cardiac patch (CCP) that can provide exogenously elastic conductive microenvironment and induce endogenously reparative microenvironment mediated by CCR2<sup>-</sup> cRMs for MI repair. This CCP exhibits suitable mechanical properties, conductivity, and high water retention, reminiscent of natural myocardium, which can actively engage in modulating CCR2<sup>-</sup> cRM renewal and their cell crosstalk. The functional CCP can promote the expression of Connexin43 between CCR2<sup>-</sup> cRMs and cardiomyocytes (CMs) and regulate paracrine signaling to activate epicardial cell epithelial-to-mesenchymal transition (EMT) toward endothelial cells using rat and Wt1<sup>CreERT2</sup> transgenic lineage tracing mice. Overall, this study provides a promising strategy to construct a synergistic reparative microenvironment for MI repair.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101932"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064196","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: 2025-01-31DOI: 10.1016/j.xcrm.2025.101933
Kristian Gurashi, Yu-Hung Wang, Fabio M R Amaral, Katherine Spence, Rachel Cant, Chi-Yuan Yao, Chien-Chin Lin, Christopher Wirth, David C Wedge, Guillermo Montalban-Bravo, Simona Colla, Hwei-Fang Tien, Tim C P Somervaille, Kiran Batta, Daniel H Wiseman
{"title":"An integrative multiparametric approach stratifies putative distinct phenotypes of blast phase chronic myelomonocytic leukemia.","authors":"Kristian Gurashi, Yu-Hung Wang, Fabio M R Amaral, Katherine Spence, Rachel Cant, Chi-Yuan Yao, Chien-Chin Lin, Christopher Wirth, David C Wedge, Guillermo Montalban-Bravo, Simona Colla, Hwei-Fang Tien, Tim C P Somervaille, Kiran Batta, Daniel H Wiseman","doi":"10.1016/j.xcrm.2025.101933","DOIUrl":"10.1016/j.xcrm.2025.101933","url":null,"abstract":"<p><p>Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) undergo transformation to a chemo-refractory blastic phase (BP-CMML). Seeking novel therapeutic approaches, we profiled blast transcriptomes from 42 BP-CMMLs, observing extensive transcriptional heterogeneity and poor alignment to current acute myeloid leukemia (AML) classifications. BP-CMMLs display distinctive transcriptomic profiles, including enrichment for quiescence and variability in drug response signatures. Integrating clinical, immunophenotype, and transcriptome parameters, Random Forest unsupervised clustering distinguishes immature and mature subtypes characterized by differential expression of transcriptional modules, oncogenes, apoptotic regulators, and patterns of surface marker expression. Subtypes differ in predicted response to AML drugs, validated ex vivo in primary samples. Iteratively refined stratification resolves a classification structure comprising five subtypes along a maturation spectrum, predictive of response to novel agents including consistent patterns for receptor tyrosine kinase (RTK), cyclin-dependent kinase (CDK), mechanistic target of rapamycin (MTOR), and mitogen-activated protein kinase (MAPK) inhibitors. Finally, we generate a prototype decision tree to stratify BP-CMML with high specificity and sensitivity, requiring validation but with potential clinical applicability to guide personalized drug selection for improved outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101933"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073936","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: 2025-01-23DOI: 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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-05DOI: 10.1016/j.xcrm.2024.101927
Hongzhen Li, Zhiheng Zhang, Zhao Shi, Siqi Zhou, Shuang Nie, Yuanyuan Yu, Lingling Zhang, Yifeng Sun, Chao Fang, Jingxiong Hu, Yiqi Niu, Kathleen Schuck, Lei Wang, Kuirong Jiang, Zipeng Lu, Christoph Kahlert, Susanne Roth, Martin Loos, Ingrid Herr, Yoshiaki Sunami, Jörg Kleeff, Helmut Friess, Maximilian Reichert, Zahra Dantes, Xiaoping Zou, Christoph W Michalski, Shanshan Shen, Bo Kong
{"title":"Disrupting AGR2/IGF1 paracrine and reciprocal signaling for pancreatic cancer therapy.","authors":"Hongzhen Li, Zhiheng Zhang, Zhao Shi, Siqi Zhou, Shuang Nie, Yuanyuan Yu, Lingling Zhang, Yifeng Sun, Chao Fang, Jingxiong Hu, Yiqi Niu, Kathleen Schuck, Lei Wang, Kuirong Jiang, Zipeng Lu, Christoph Kahlert, Susanne Roth, Martin Loos, Ingrid Herr, Yoshiaki Sunami, Jörg Kleeff, Helmut Friess, Maximilian Reichert, Zahra Dantes, Xiaoping Zou, Christoph W Michalski, Shanshan Shen, Bo Kong","doi":"10.1016/j.xcrm.2024.101927","DOIUrl":"10.1016/j.xcrm.2024.101927","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and characterized by pronounced desmoplasia. PDAC cells communicate with cancer-associated fibroblasts (CAFs) in a paracrine/reciprocal manner, substantially promoting tumor growth and desmoplastic responses. This study highlights the critical role of anterior gradient 2 (AGR2), an endoplasmic reticulum protein disulfide isomerase, secreted by PDAC cells to activate CAFs via the Wnt signaling pathway. Activated CAFs, in turn, secrete insulin-like growth factor 1 (IGF1), which enhances AGR2 expression and secretion in PDAC cells through the IGF1 receptor (IGF1R)/c-JUN axis. Within PDAC cells, AGR2 acts as a thioredoxin, aiding the folding and cell surface presentation of IGF1R, essential for PDAC's response to CAF-derived IGF1. This reciprocal AGR2/IGF1 signaling loop intensifies desmoplasia, immunosuppression, and tumorigenesis, creating a harmful feedback loop. Targeting both pathways disrupts this interaction, reduces desmoplasia, and restores anti-tumor immunity in preclinical models, offering a promising therapeutic strategy against PDAC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101927"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363602","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: 2025-02-05DOI: 10.1016/j.xcrm.2025.101937
Sara Arce-Gallego, Pablo Cresta Morgado, Luisa Delgado-Serrano, Sara Simonetti, Macarena Gonzalez, Paula Romero-Lozano, David Marmolejo, Rafael Morales-Barrera, Gisela Mir Arnau, Maria Eugenia Semidey, Daniel Aguilar, Sarai Cordoba-Terreros, Richard Mast, Matias de Albert, Jacques Planas, Mercè Cuadras, Xavier Maldonado, Cristina Suarez, Irene Casanova-Salas, Mariona Figols, Sara Cros, Alba Mas, Lara Nonell, Rodrigo Dienstmann, Paolo Nuciforo, Ana Vivancos, Alba Llop-Guevara, Joan Carles, Violeta Serra, Joaquin Mateo
{"title":"Homologous recombination repair status in metastatic prostate cancer by next-generation sequencing and functional immunofluorescence.","authors":"Sara Arce-Gallego, Pablo Cresta Morgado, Luisa Delgado-Serrano, Sara Simonetti, Macarena Gonzalez, Paula Romero-Lozano, David Marmolejo, Rafael Morales-Barrera, Gisela Mir Arnau, Maria Eugenia Semidey, Daniel Aguilar, Sarai Cordoba-Terreros, Richard Mast, Matias de Albert, Jacques Planas, Mercè Cuadras, Xavier Maldonado, Cristina Suarez, Irene Casanova-Salas, Mariona Figols, Sara Cros, Alba Mas, Lara Nonell, Rodrigo Dienstmann, Paolo Nuciforo, Ana Vivancos, Alba Llop-Guevara, Joan Carles, Violeta Serra, Joaquin Mateo","doi":"10.1016/j.xcrm.2025.101937","DOIUrl":"10.1016/j.xcrm.2025.101937","url":null,"abstract":"<p><p>Metastatic prostate cancer (mPC) is enriched for homologous recombination repair (HRR) gene alterations, which have prognostic and predictive value. Routine clinical implementation of next-generation sequencing (NGS) is still limited. We investigated the association between genomic and functional loss of HRR, using NGS and RAD51 immunofluorescence (RAD51-IF) in 219 primary or metastatic biopsies from 187 patients with stage IV prostate cancer. NGS showed frequent genomic alterations in TP53 (40%), AR (15%), PTEN (14%), FOXA1 (12%), MYC (10%), BRCA2 (9%), ATM (8%), and BRCA1 (2%). We pursued RAD51-IF in 206 samples; of those, 139/206 (67%) were evaluable. 21% of samples had RAD51-low score compatible with HRR deficiency (HRD). RAD51-IF showed high sensitivity (71%) and specificity (86%) for BRCA1/2 alterations. Patients with RAD51-low scores experienced longer progression-free survival (PFS) on poly(ADP-ribose) polymerase inhibitors (PARPi) or platinum chemotherapy. RAD51-IF is feasible in routine clinical samples from patients with mPC and is associated with clinically relevant HRR gene alterations.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101937"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363770","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}
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