Journal of Biomedical Science最新文献

{"title":"HBV DNA integration and somatic mutations in HCC patients with HBV-HCV dual infection reveals profiles intermediate between HBV- and HCV-related HCC.","authors":"Chiao-Ling Li, Chia-Lang Hsu, You-Yu Lin, Ming-Chih Ho, Rey-Heng Hu, Sheng-Tai Tzeng, Ya-Chun Wang, Yasuhito Tanaka, Pei-Jer Chen, Shiou-Hwei Yeh","doi":"10.1186/s12929-024-01094-7","DOIUrl":"10.1186/s12929-024-01094-7","url":null,"abstract":"<p><strong>Background: </strong>In regions with a high prevalence of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, coinfected patients face a heightened risk of developing hepatocellular carcinoma (HCC), termed HBV/HCV-related HCC (HBCV-HCC). We aimed to investigate the contribution of preexisting chronic hepatitis B (CHB) and subsequent chronic hepatitis C (CHC) to the development of HBCV-HCC.</p><p><strong>Methods: </strong>We examined HBV's involvement in 93 HBCV-HCC cases by analyzing HBV DNA integration as an indicator of HCC originating from HBV-infected hepatocytes, compared with 164 HBV-HCCs and 56 HCV-HCCs as controls.</p><p><strong>Results: </strong>Next generation sequencing revealed that 55% of HBCV-HCCs exhibited clonal HBV integration, which falls between the rates observed in HBV-HCCs (88%) and HCV-HCCs (7%), with similar integration patterns to HBV-HCCs. Common HCC somatic mutation analysis indicated HCV superinfection in HBCV-HCCs correlated with increased mutation rates in the telomerase reverse transcriptase (TERT) promoter and beta-catenin genes. Transcriptome analysis showed a prevalence of replicating HCV over HBV in HBCV-HCCs, with preexisting HBV exerting a proliferative role. The comparison of clinical characteristics revealed similarities between HBCV-HCC and HCV-HCC patients, including later onset for HBCV-HCC, possibly due to HCV superinfection slowing carcinogenesis. Notably, HBCV-HCCs with the same driver mutation, HBV integration at the TERT promoter, tended to develop later and showed a better prognosis post-tumor resection than HBV-HCCs.</p><p><strong>Conclusions: </strong>Our findings shed light on the interplay between preexisting CHB and subsequent CHC in elevating the risk of HBCV-HCC. These insights are crucial for understanding viral etiology-specific carcinogenesis and guiding surveillance policies for HBCV-HCC post-antiviral therapy.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"2"},"PeriodicalIF":9.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reassessing the roles of oxidative DNA base lesion 8-oxoGua and repair enzyme OGG1 in tumorigenesis.","authors":"Jing Wang, Chunshuang Li, Jinling Han, Yaoyao Xue, Xu Zheng, Ruoxi Wang, Zsolt Radak, Yusaku Nakabeppu, Istvan Boldogh, Xueqing Ba","doi":"10.1186/s12929-024-01093-8","DOIUrl":"10.1186/s12929-024-01093-8","url":null,"abstract":"<p><p>ROS cause multiple forms of DNA damage, and among them, 8-oxoguanine (8-oxoGua), an oxidized product of guanine, is one of the most abundant. If left unrepaired, 8-oxoGua may pair with A instead of C, leading to a mutation of G: C to T: A during DNA replication. 8-Oxoguanine DNA glycosylase 1 (OGG1) is a tailored repair enzyme that recognizes 8-oxoGua in DNA duplex and initiates the base excision repair (BER) pathway to remove the lesion and ensure the fidelity of the genome. The accumulation of genomic 8-oxoGua and the dysfunction of OGG1 is readily linked to mutagenesis, and subsequently aging-related diseases and tumorigenesis; however, the direct experimental evidence has long been lacking. Recently, a series of studies have shown that guanine oxidation in the genome has a conservative bias, with the tendency to occur in the regulatory regions, thus, 8-oxoGua is not only a lesion to be repaired, but also an epigenetic modification. In this regard, OGG1 is a specific reader of this base modification. Substrate recognition and/or excision by OGG1 can cause DNA conformation changes, affect chromatin modifications, thereby modulating the transcription of genes involved in a variety of cellular processes, including inflammation, cell proliferation, differentiation, and apoptosis. Thus, in addition to the potential mutagenicity, 8-oxoGua may contribute to tumor development and progression through the altered gene expression stemming from its epigenetic effects.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"1"},"PeriodicalIF":9.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11689541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulating the regulators: long non-coding RNAs as autophagic controllers in chronic disease management.","authors":"Aviral Kumar, Kenneth Chun-Hong Yap, Bandari BharathwajChetty, Juncheng Lyu, Mangala Hegde, Mohamed Abbas, Mohammed S Alqahtani, Soham Khadlikar, Ali Zarrabi, Arezoo Khosravi, Alan Prem Kumar, Ajaikumar B Kunnumakkara","doi":"10.1186/s12929-024-01092-9","DOIUrl":"10.1186/s12929-024-01092-9","url":null,"abstract":"<p><p>The increasing prevalence of chronic diseases and their associated morbidities demands a deeper understanding of underlying mechanism and causative factors, with the hope of developing novel therapeutic strategies. Autophagy, a conserved biological process, involves the degradation of damaged organelles or protein aggregates to maintain cellular homeostasis. Disruption of this crucial process leads to increased genomic instability, accumulation of reactive oxygen species (ROS), decreased mitochondrial functions, and suppression of ubiquitination, leading to overall decline in quality of intracellular components. Such deregulation has been implicated in a wide range of pathological conditions such as cancer, cardiovascular, inflammatory, and neurological disorders. This review explores the role of long non-coding RNAs (lncRNAs) as modulators of transcriptional and post-transcriptional gene expression, regulating diverse physiological process like proliferation, development, immunity, and metabolism. Moreover, lncRNAs are known to sequester autophagy related microRNAs by functioning as competing endogenous RNAs (ceRNAs), thereby regulating this vital process. In the present review, we delineate the multitiered regulation of lncRNAs in the autophagic dysfunction of various pathological diseases. Moreover, by highlighting recent findings on the modulation of lncRNAs in different stages of autophagy, and the emerging clinical landscape that recognizes lncRNAs in disease diagnosis and therapy, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in clinical settings of different stages of autophagic process by regulating ATG and its target genes. This focus on lncRNAs could lead to breakthroughs in personalized medicine, offering new avenues for diagnosis and treatment of complex diseases.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"105"},"PeriodicalIF":9.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome.","authors":"Keli Kuang, Chunyan Li, Fatlinda Maksut, Deepanjan Ghosh, Robin Vinck, Maolin Wang, Joel Poupon, Run Xiang, Wen Li, Fei Li, Zhu Wang, Junrong Du, Marie-Paule Teulade-Fichou, Gilles Gasser, Sophie Bombard, Tao Jia","doi":"10.1186/s12929-024-01107-5","DOIUrl":"10.1186/s12929-024-01107-5","url":null,"abstract":"","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"104"},"PeriodicalIF":9.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11648279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclophostin and Cyclipostins analogues counteract macrolide-induced resistance mediated by erm(41) in Mycobacterium abscessus.","authors":"Morgane Sarrazin, Isabelle Poncin, Patrick Fourquet, Stéphane Audebert, Luc Camoin, Yann Denis, Pierre Santucci, Christopher D Spilling, Laurent Kremer, Vincent Le Moigne, Jean-Louis Herrmann, Jean-François Cavalier, Stéphane Canaan","doi":"10.1186/s12929-024-01091-w","DOIUrl":"10.1186/s12929-024-01091-w","url":null,"abstract":"<p><strong>Background: </strong>Mycobacterium abscessus is an emerging pathogen causing severe pulmonary infections, particularly in individuals with underlying conditions, such as cystic fibrosis or chronic obstructive pulmonary disease. Macrolides, such as clarithromycin (CLR) or azithromycin (AZM), represent the cornerstone of antibiotherapy against the M. abscessus species. However, prolonged exposure to these macrolides can induce of Erm(41)-mediated resistance, limiting their spectrum of activity and leading to therapeutic failure. Therefore, inhibiting Erm(41) could thwart this resistance mechanism to maintain macrolide susceptibility, thus increasing the rate of treatment success. In our previous study, the Erm(41) methyltransferase was identified as a possible target enzyme of Cyclipostins and Cyclophostin compounds (CyC).</p><p><strong>Methods: </strong>Herein, we exploited this feature to evaluate the in vitro activity of CLR and AZM in combination with different CyC via the checkerboard assay on macrolide-susceptible and induced macrolide-resistant M. abscessus strains selected in vitro following exposure CLR and AZM.</p><p><strong>Results: </strong>Our results emphasize the use of the CyC to prevent/overcome Erm(41)‑induced resistance and to restore macrolide susceptibility.</p><p><strong>Conclusion: </strong>This work should expand our therapeutic arsenal in the fight against a antibioticresistant mycobacterial species and could provide the opportunity to revisit the therapeutic regimen for combating M. abscessus pulmonary infections in patients, and particularly in erm(41)-positive strains.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"103"},"PeriodicalIF":9.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of glucagon-like peptide-1 receptor agonists in Alzheimer's disease and Parkinson's disease.","authors":"Chien-Tai Hong, Jia-Hung Chen, Chaur-Jong Hu","doi":"10.1186/s12929-024-01090-x","DOIUrl":"10.1186/s12929-024-01090-x","url":null,"abstract":"<p><p>Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common complications of diabetes, arising from insulin resistance, inflammation, and other pathological processes in the central nervous system. The potential of numerous antidiabetic agents to modify neurodegenerative disease progression, both preclinically and clinically, has been assessed. These agents may provide additional therapeutic benefits beyond glycemic control. Introduced in the twenty-first century, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of antidiabetic drugs noted not only for their potent glucose-lowering effects but also for their cardiovascular and renal protective benefits. Various GLP-1RAs have been demonstrated to have significant benefits in in vitro and in vivo models of neurodegenerative diseases through modulating a variety of pathogenic mechanisms, including neuroinflammation, autophagy, mitochondrial dysfunction, and the abnormal phosphorylation of pathognomonic proteins. These agents also have substantial protective effects on cognitive and behavioral functions, such as motor function. However, clinical trials investigating GLP-1RAs in diseases such as AD, PD, mild cognitive impairment, psychiatric disorders, and diabetes have yielded mixed results for cognitive and motor function. This review examines the link between diabetes and neurodegenerative diseases, explores the effects of antidiabetic agents on neurodegeneration, provides a concise overview of the GLP-1 pathway, and discusses both preclinical and clinical trial outcomes of GLP-1RAs for neurodegenerative diseases, including their effects on cognition in AD and PD. This review also proposed new strategies for the design of future clinical trials on GLP-1 RAs for both AD and PD.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"102"},"PeriodicalIF":9.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dental pulp mesenchymal stem cell (DPSCs)-derived soluble factors, produced under hypoxic conditions, support angiogenesis via endothelial cell activation and generation of M2-like macrophages.","authors":"Ludovica Barone, Martina Cucchiara, Maria Teresa Palano, Barbara Bassani, Matteo Gallazzi, Federica Rossi, Mario Raspanti, Piero Antonio Zecca, Gianluca De Antoni, Christina Pagiatakis, Roberto Papait, Giovanni Bernardini, Antonino Bruno, Rosalba Gornati","doi":"10.1186/s12929-024-01087-6","DOIUrl":"10.1186/s12929-024-01087-6","url":null,"abstract":"<p><strong>Background: </strong>Cell therapy has emerged as a revolutionary tool to repair damaged tissues by restoration of an adequate vasculature. Dental Pulp stem cells (DPSC), due to their easy biological access, ex vivo properties, and ability to support angiogenesis have been largely explored in regenerative medicine.</p><p><strong>Methods: </strong>Here, we tested the capability of Dental Pulp Stem Cell-Conditioned medium (DPSC-CM), produced in normoxic (DPSC-CM Normox) or hypoxic (DPSC-CM Hypox) conditions, to support angiogenesis via their soluble factors. CMs were characterized by a secretome protein array, then used for in vivo and in vitro experiments. In in vivo experiments, DPSC-CMs were associated to an Ultimatrix sponge and injected in nude mice. After excision, Ultimatrix were assayed by immunohistochemistry, electron microscopy and flow cytometry, to evaluate the presence of endothelial, stromal, and immune cells. For in vitro procedures, DPSC-CMs were used on human umbilical-vein endothelial cells (HUVECs), to test their effects on cell adhesion, migration, tube formation, and on their capability to recruit human CD14⁺ monocytes.</p><p><strong>Results: </strong>We found that DPSC-CM Hypox exert stronger pro-angiogenic activities, compared with DPSC-CM Normox, by increasing the frequency of CD31⁺ endothelial cells, the number of vessels and hemoglobin content in the Ultimatrix sponges. We observed that Utimatrix sponges associated with DPSC-CM Hypox or DPSC-CM Normox shared similar capability to recruit CD45^- stromal cells, CD45⁺ leukocytes, F4/80⁺ macrophages, CD80⁺ M1-macrophages and CD206⁺ M2-macropages. We also observed that DPSC-CM Hypox and DPSC-CM Normox have similar capabilities to support HUVEC adhesion, migration, induction of a pro-angiogenic gene signature and the generation of capillary-like structures, together with the ability to recruit human CD14⁺ monocytes.</p><p><strong>Conclusions: </strong>Our results provide evidence that DPSCs-CM, produced under hypoxic conditions, can be proposed as a tool able to support angiogenesis via macrophage polarization, suggesting its use to overcome the issues and restrictions associated with the use of staminal cells.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"99"},"PeriodicalIF":9.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring paraptosis as a therapeutic approach in cancer treatment.","authors":"Ling-Chu Chang, Shih-Kai Chiang, Shuen-Ei Chen, Mien-Chie Hung","doi":"10.1186/s12929-024-01089-4","DOIUrl":"10.1186/s12929-024-01089-4","url":null,"abstract":"<p><p>A variety of cell death pathways play critical roles in the onset and progression of multiple diseases. Paraptosis, a unique form of programmed cell death, has gained significant attention in recent years. Unlike apoptosis and necrosis, paraptosis is characterized by cytoplasmic vacuolization, swelling of the endoplasmic reticulum and mitochondria, and the absence of caspase activation. Numerous natural products, synthetic compounds, and newly launched nanomedicines have been demonstrated to prime cell death through the paraptotic program and may offer novel therapeutic strategies for cancer treatment. This review summarizes recent findings, delineates the intricate network of signaling pathways underlying paraptosis, and discusses the potential therapeutic implications of targeting paraptosis in cancer treatment. The aim of this review is to expand our understanding of this unique cell death process and explore the potential therapeutic implications of targeting paraptosis in cancer treatment.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"101"},"PeriodicalIF":9.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular consequences of FOXF1 missense mutations associated with alveolar capillary dysplasia with misalignment of pulmonary veins.","authors":"G G Edel, M van Kempen, A Boerema-de Munck, C N Huisman, C A P Naalden, R W W Brouwer, S Koornneef, W F J van IJcken, R M H Wijnen, R J Rottier","doi":"10.1186/s12929-024-01088-5","DOIUrl":"10.1186/s12929-024-01088-5","url":null,"abstract":"<p><strong>Background: </strong>Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a fatal congenital lung disorder strongly associated with genomic alterations in the Forkhead box F1 (FOXF1) gene and its regulatory region. However, little is known about how FOXF1 genomic alterations cause ACD/MPV and what molecular mechanisms are affected by these mutations. Therefore, the effect of ACD/MPV patient-specific mutations in the FOXF1 gene on the molecular function of FOXF1 was studied.</p><p><strong>Methods: </strong>Epitope-tagged FOXF1 constructs containing one of the ACD/MPV-associated mutations were expressed in mammalian cell lines to study the effect of FOXF1 mutations on protein function. EMSA binding assays and luciferase assays were performed to study the effect on target gene binding and activation. Immunoprecipitation followed by SDS‒PAGE and western blotting were used to study protein‒protein interactions. Protein phosphorylation was studied using phos-tag western blotting.</p><p><strong>Results: </strong>An overview of the localization of ACD/MPV-associated FOXF1 mutations revealed that the G91-S101 region was frequently mutated. A three-dimensional model of the forkhead DNA-binding domain of FOXF1 showed that the G91-S101 region consists of an α-helix and is predicted to be important for DNA binding. We showed that FOXF1 missense mutations in this region differentially affect the DNA binding of the FOXF1 protein and influence the transcriptional regulation of target genes depending on the location of the mutation. Furthermore, we showed that some of these mutations can affect the FOXF1 protein at the posttranscriptional level, as shown by altered phosphorylation by MST1 and MST2 kinases.</p><p><strong>Conclusion: </strong>Missense mutations in the coding region of the FOXF1 gene alter the molecular function of the FOXF1 protein at multiple levels, such as phosphorylation, DNA binding and target gene activation. These results indicate that FOXF1 molecular pathways may be differentially affected in ACD/MPV patients carrying missense mutations in the DNA-binding domain and may explain the phenotypic heterogeneity of ACD/MPV.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"100"},"PeriodicalIF":9.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD81-guided heterologous EVs present heterogeneous interactions with breast cancer cells.","authors":"Elena Gurrieri, Giulia Carradori, Michela Roccuzzo, Michael Pancher, Daniele Peroni, Romina Belli, Caterina Trevisan, Michela Notarangelo, Wen-Qiu Huang, Agata S A Carreira, Alessandro Quattrone, Guido Jenster, Timo L M Ten Hagen, Vito Giuseppe D'Agostino","doi":"10.1186/s12929-024-01084-9","DOIUrl":"https://doi.org/10.1186/s12929-024-01084-9","url":null,"abstract":"<p><strong>Background: </strong>Extracellular vesicles (EVs) are cell-secreted particles conceived as natural vehicles for intercellular communication. The capacity to entrap heterogeneous molecular cargoes and target specific cell populations through EV functionalization promises advancements in biomedical applications. However, the efficiency of the obtained EVs, the contribution of cell-exposed receptors to EV interactions, and the predictability of functional cargo release with potential sharing of high molecular weight recombinant mRNAs are crucial for advancing heterologous EVs in targeted therapy applications.</p><p><strong>Methods: </strong>In this work, we selected the popular EV marker CD81 as a transmembrane guide for fusion proteins with a C-terminal GFP reporter encompassing or not Trastuzumab light chains targeting the HER2 receptor. We performed high-content imaging analyses to track EV-cell interactions, including isogenic breast cancer cells with manipulated HER2 expression. We validated the functional cargo delivery of recombinant EVs carrying doxorubicin upon EV-donor cell treatment. Then, we performed an in vivo study using JIMT-1 cells commonly used as HER2-refractory, trastuzumab-resistant model to detect a more than 2000 nt length recombinant mRNA in engrafted tumors.</p><p><strong>Results: </strong>Fusion proteins participated in vesicular trafficking dynamics and accumulated on secreted EVs according to their expression levels in HEK293T cells. Despite the presence of GFP, secreted EV populations retained a HER2 receptor-binding capacity and were used to track EV-cell interactions. In time-frames where the global EV distribution did not change between HER2-positive (SK-BR-3) or -negative (MDA-MB-231) breast cancer cell lines, the HER2 exposure in isogenic cells remarkably affected the tropism of heterologous EVs, demonstrating the specificity of antiHER2 EVs representing about 20% of secreted bulk vesicles. The specific interaction strongly correlated with improved cell-killing activity of doxorubicin-EVs in MDA-MB-231 ectopically expressing HER2 and reduced toxicity in SK-BR-3 with a knocked-out HER2 receptor, overcoming the effects of the free drug. Interestingly, the fusion protein-corresponding transcripts present as full-length mRNAs in recombinant EVs could reach orthotopic breast tumors in JIMT-1-xenografted mice, improving our sensitivity in detecting penetrant cargoes in tissue biopsies.</p><p><strong>Conclusions: </strong>This study highlights the quantitative aspects underlying the creation of a platform for secreted heterologous EVs and shows the limits of single receptor-ligand interactions behind EV-cell engagement mechanisms, which now become the pivotal step to predict functional tropism and design new generations of EV-based nanovehicles.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"92"},"PeriodicalIF":9.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}