Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Reprogramming the breast tumor immune microenvironment: cold-to-hot transition for enhanced immunotherapy.","authors":"Saber Imani, Reyhaneh Farghadani, Ghazaal Roozitalab, Mazaher Maghsoudloo, Mahdieh Emadi, Atefeh Moradi, Behnaz Abedi, Parham Jabbarzadeh Kaboli","doi":"10.1186/s13046-025-03394-8","DOIUrl":"https://doi.org/10.1186/s13046-025-03394-8","url":null,"abstract":"<p><p>This review discusses reprogramming the breast tumor immune microenvironment from an immunosuppressive cold state to an immunologically active hot state. A complex interplay is revealed, in which the accumulation of metabolic byproducts-such as lactate, reactive oxygen species (ROS), and ammonia-is shown to impair T-cell function and promote tumor immune escape. It is demonstrated that the tumor microenvironment (TME) is dominated by immunosuppressive cytokines, including interleukin-10 (IL-10), transforming growth factorβ (TGFβ), and IL-35. Notably, IL-35 is produced by regulatory T cells and breast cancer cells. The conversion of conventional T cells into IL-35-producing induced regulatory T cells, along with the inhibition of pro-inflammatory cytokine secretion, contributes to the suppression of anti-tumor immunity. It is further demonstrated that key immune checkpoint molecules-such as PD-1, PDL1, CTLA-4, TIM-3, LAG-3, and TIGIT-are upregulated within the TME, leading to Tcell exhaustion and diminished immune responses. The blockade of these checkpoints is shown to restore T-cell functionality and is proposed as a strategy to convert cold tumors into hot ones with robust effector cell infiltration. The therapeutic potential of chimeric antigen receptor (CAR)T cell therapy is also explored, and targeting specific tumor-associated antigens, such as glycoproteins and receptor tyrosine kinases, is highlighted. It is suggested that CART cell efficacy can be enhanced by combining these cells with immune checkpoint inhibitors and other immunomodulatory agents, thereby overcoming the barriers imposed by the immunosuppressive TME. Moreover, the role of the microbiome in regulating estrogen metabolism and systemic inflammation is reviewed. Alterations in the gut microbiota are shown to affect the TME, and microbiome-based interventions are proposed as an additional means to facilitate the cold-to-hot transition. It is concluded that by targeting the metabolic and immunological pathways that underpin immune suppression-through combination strategies involving checkpoint blockade, CART cell therapies, and microbiome modulation-the conversion of the breast TME from cold to hot can be achieved. This reprogramming is anticipated to enhance immune cell infiltration and function, thereby improving the overall efficacy of immunotherapies and leading to better clinical outcomes for breast cancer patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"131"},"PeriodicalIF":11.4,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058745","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":"7aaRGD - a novel SPP1/integrin signaling-blocking peptide reverses immunosuppression and improves anti-PD-1 immunotherapy outcomes in experimental gliomas.","authors":"Aleksandra Ellert-Miklaszewska, Paulina Pilanc, Katarzyna Poleszak, Adria-Jaume Roura, Salwador Cyranowski, Mitrajit Ghosh, Szymon Baluszek, Maria Pasierbinska, Bartłomiej Gielniewski, Julian Swatler, Yuliana Hovorova, Kamil Wojnicki, Bozena Kaminska","doi":"10.1186/s13046-025-03393-9","DOIUrl":"https://doi.org/10.1186/s13046-025-03393-9","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) present clinical benefits in many cancer patients but invariably fail in glioblastoma (GBM), the most common and deadly primary brain tumor. The lack of ICIs efficacy in GBM is attributed to the accumulation of tumor-reprogrammed glioma-associated myeloid cells (GAMs) that create a \"cold\" immunosuppressive tumor microenvironment (TME), impeding the infiltration and activation of effector T cells. GBM-derived αvβ3/αvβ5-integrin ligands, including SPP1, were shown to mediate the emergence of GAMs. We hypothesized that a combination strategy aiming to block the reprogramming of GAMs using a synthetic 7aaRGD peptide that targets SPP1/integrin signaling might overcome resistance to ICIs and reinvigorate anti-tumor immunity.</p><p><strong>Methods: </strong>Matrigel invasion assay was used to test the efficacy of 7aaRGD in glioma-microglia co-cultures. We determined the impact of 7aaRGD, administered as a monotherapy or combined with PD-1 blockade, on tumor growth, GAMs accumulation and phenotypes, arginase-1 levels and neovasculature in experimental gliomas. The effects of treatments on the tumor immune landscape were dissected using multiparameter flow cytometry, immunocytochemistry, cytokine profiling and RNA-seq analysis of sorted GAMs followed by CITE-seq based data deconvolution.</p><p><strong>Results: </strong>7aaRGD efficiently blocked microglia-dependent invasion of human and mouse glioma cells in vitro. Intratumorally delivered 7aaRGD alone did not reduce tumor growth in orthotopic gliomas but prevented the emergence of immunosuppressive GAMs and led to normalization of peritumoral blood vessels. Combining 7aaRGD with anti-PD-1 antibody resulted in reduced tumor growth, with an increase in the number of proliferating, interferon-ɣ producing CD8⁺T cells and depletion of regulatory T cells. Transcriptomic profiles of myeloid cells were altered by the combined treatment, reflecting the restored \"hot\" inflammatory TME and boosted immunotherapy responses. Intratumoral administration of 7aaRGD similarly modified the phenotypes of GAMs in human U87-MG gliomas in immunocompromised mice. Exploration of transcriptomic datasets revealed that high expression of integrin receptor coding genes in pre-treatment biopsies was associated with a poorer response to immune check-point blockade in patients with several types of cancers.</p><p><strong>Conclusions: </strong>We demonstrate that combining the blockade of SPP1/integrin signaling with ICIs modifies innate immunity and reinvigorates adaptive antitumor responses, which paves the way to improve immunotherapy outcomes in GBM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"132"},"PeriodicalIF":11.4,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042254","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":"A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer.","authors":"Juliana Calheiros, Rita Silva, Filipa Barbosa, João Morais, Sara Reis Moura, Sofia Almeida, Elena Fiorini, Silva Mulhovo, Tatiana Q Aguiar, Tao Wang, Sara Ricardo, Maria Inês Almeida, Lucília Domingues, Sonia A Melo, Vincenzo Corbo, Maria-José U Ferreira, Lucília Saraiva","doi":"10.1186/s13046-025-03389-5","DOIUrl":"https://doi.org/10.1186/s13046-025-03389-5","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is among the cancer types with poorest prognosis and survival rates primarily due to resistance to standard-of-care therapies, including gemcitabine (GEM) and olaparib. Particularly, wild-type (wt)BRCA tumours, the most prevalent in PDAC, are more resistant to DNA-targeting agents like olaparib, restraining their clinical application. Recently, we disclosed a monoterpene indole alkaloid derivative (BBIT20) as a new inhibitor of homologous recombination (HR) DNA repair with anticancer activity in breast and ovarian cancer. Since inhibition of DNA repair enhances the sensitivity of cancer cells to chemotherapy, we aimed to investigate the anticancer potential of BBIT20 against PDAC, particularly carrying wtBRCA.</p><p><strong>Methods: </strong>In vitro and in vivo PDAC models, particularly human cell lines (including GEM-resistant PDAC cells), patient-derived organoids and xenograft mice of PDAC were used to evaluate the anticancer potential of BBIT20, alone and in combination with GEM or olaparib. Disruption of the BRCA1-BARD1 interaction by BBIT20 was assessed by co-immunoprecipitation, immunofluorescence and yeast two-hybrid assay.</p><p><strong>Results: </strong>The potent antiproliferative activity of BBIT20, superior to olaparib, was demonstrated in PDAC cells regardless of BRCA status, by inducing cell cycle arrest, apoptosis, and DNA damage, while downregulating HR. The disruption of DNA double-strand breaks repair by BBIT20 was further reinforced by non-homologous end joining (NHEJ) suppression. The inhibition of BRCA1-BARD1 heterodimer by BBIT20 was demonstrated in PDAC cells and confirmed in a yeast two-hybrid assay. In GEM-resistant PDAC cells, BBIT20 showed potent antiproliferative, anti-migratory and anti-invasive activity, overcoming GEM resistance by inhibiting the multidrug resistance P-glycoprotein, upregulating the intracellular GEM-transporter ENT1, and downregulating GEM resistance-related microRNA-20a and GEM metabolism enzymes as RRM1/2. Furthermore, BBIT20 did not induce resistance in PDAC cells. It inhibited the growth of patient-derived PDAC organoids, by inducing apoptosis, repressing HR, and potentiating olaparib and GEM cytotoxicity. The enhancement of olaparib antitumor activity by BBIT20 was confirmed in xenograft mice of PDAC. Notably, it hindered tumour growth and liver metastasis formation, improving survival of orthotopic xenograft mice of PDAC. Furthermore, its potential as a stroma-targeting agent, reducing fibrotic extracellular matrix and overcoming desmoplasia, associated with an enhancement of immune cell response by depleting PD-L1 expression in tumour tissues, renders BBIT20 even more appealing for combination therapy, particularly with immunotherapy.</p><p><strong>Conclusion: </strong>These findings underscore the great potential of BBIT20 as a novel multifaceted anticancer drug candidate for PDAC treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"129"},"PeriodicalIF":11.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025193","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":"Exploring RNA binding proteins in hepatocellular carcinoma: insights into mechanisms and therapeutic potential.","authors":"Xing Ren, Wenna Yang, Xiuli Yan, Hui Zhang","doi":"10.1186/s13046-025-03395-7","DOIUrl":"https://doi.org/10.1186/s13046-025-03395-7","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, is linked to elevated global incidence and mortality rates. Elucidating the intricate molecular pathways that drive the progression of HCC is imperative for devising targeted and effective therapeutic interventions. RNA-binding proteins (RBPs) serve as pivotal regulators of post-transcriptional processes, influencing various cellular functions. This review endeavors to provide a comprehensive analysis of the expression, function, and potential implications of RBPs in HCC. We discuss the classification and diverse roles of RBPs, with a particular focus on key RBPs implicated in HCC and their association with disease progression. Additionally, we explore the mechanisms by which RBPs contribute to HCC, including their impact on gene expression, cell proliferation, cell metastasis, angiogenesis, signaling pathways, and post-transcriptional modifications. Importantly, we examine the potential of RBPs as therapeutic targets and prognostic biomarkers, offering insights into their relevance in HCC treatment. Finally, we outline future research directions, emphasizing the need for further investigation into the functional mechanisms of RBPs and their clinical translation for personalized HCC therapy. This comprehensive review highlights the pivotal role of RBPs in HCC and their potential as novel therapeutic avenues to improve patient outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"130"},"PeriodicalIF":11.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042654","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":"Advanced organoid models for targeting Kras-driven lung adenocarcinoma in drug discovery and combination therapy.","authors":"İsa Taş, Ruben Jacobs, Juliane Albrecht, Sebastian A Barrientos, Josephine Åberg, Wondossen Sime, Hans Brunnström, Helena Persson, Julhash U Kazi, Ramin Massoumi","doi":"10.1186/s13046-025-03385-9","DOIUrl":"https://doi.org/10.1186/s13046-025-03385-9","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer remains one of the most challenging diseases to treat due to its heterogeneity. Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) mutations are genetic drivers in numerous cancer types including lung adenocarcinoma (LUAD). Despite recent advances in KRAS-targeted therapies, treatment resistance and limited therapeutic options necessitate advanced preclinical models, such as organoids, to identify personalized cancer therapies by screening novel therapeutic strategies and synergistic drug combinations.</p><p><strong>Results: </strong>We established LUAD in genetically engineered mouse (GEM) models of Kras^G12V & Trp53 ^Δex2-10 (KP) and KP with Ctnnb1^Δex3 mutation (KPC). Tumor-derived organoids from these models recapitulated the genomic landscape and histopathological characteristics of their parental tumors. The organoids displayed tumorigenic potential when implanted in immunocompromised mice, forming tumors in contrast to unlike healthy lung-derived organoids. Drug screening identified effective kinase inhibitors and DNA methyltransferase (DNMT) inhibitors against the organoids. Notably, the combination of these drugs exhibited the highest synergy in KPC organoids.</p><p><strong>Conclusion: </strong>We successfully developed LUAD organoids harboring Kras mutations and identified multiple potential therapeutic agents targeting these cells. Furthermore, we demonstrated the effectiveness of a DNMT inhibitor-based combination therapy, presenting a promising strategy for this challenging lung cancer subtype.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"128"},"PeriodicalIF":11.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005780","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":"MicroRNA in cancer therapy: breakthroughs and challenges in early clinical applications.","authors":"Maria Teresa Di Martino, Pierosandro Tagliaferri, Pierfrancesco Tassone","doi":"10.1186/s13046-025-03391-x","DOIUrl":"https://doi.org/10.1186/s13046-025-03391-x","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) have emerged as pivotal regulators in cancer biology, influencing tumorigenesis, progression, and resistance to therapy. Their ability to modulate multiple oncogenic and tumor-suppressive pathways positions them as promising therapeutic tools or targets. This review examines the dual role of miRNAs in solid and hematological malignancies, starting from their dysregulation in various cancer types. Therapeutic approaches, including miRNA replacement and inhibition strategies, are discussed alongside innovative delivery systems such as lipid nanoparticles and exosomes. Despite their transformative potential, challenges persist, including off-target effects, immune activation, and delivery inefficiencies. Recent clinical trials demonstrate both progress and hurdles, underscoring the need for advanced strategies to optimize specificity and minimize toxicity. This review provides an updated comprehensive overview of the current landscape of miRNA-based therapies under early clinical investigation and explores future directions for integrating these approaches into precision oncology.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"126"},"PeriodicalIF":11.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047844","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":"Cancer-associated fibroblasts as a potential novel liquid biopsy marker in cancer patients.","authors":"Franziska Weber, Kim-Lea Reese, Klaus Pantel, Daniel J Smit","doi":"10.1186/s13046-025-03387-7","DOIUrl":"https://doi.org/10.1186/s13046-025-03387-7","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are tissue residing cells within the tumor microenvironment (TME). Stromal CAFs have been shown to be associated with poor prognosis and tumor progression in several solid tumor entities. Although the molecular mechanisms are not fully understood yet, a critical role within the TME through direct interaction with the tumor cells as well as other cells has been proposed. While most studies on CAFs focus on stromal CAFs, recent reports highlight the possibility of detecting circulating CAFs (cCAFs) in the blood. In contrast to invasive tissue biopsies for stromal CAF characterization, liquid biopsy allows a minimally invasive isolation of cCAFs. Furthermore, liquid biopsy methods could enable continuous monitoring of cCAFs in cancer patients and therefore may present a novel biomarker for solid tumors. In this work, we present an overview of cCAF studies currently available and summarize the liquid biopsy techniques for cCAF isolation and detection. Moreover, the future research directions in the emerging field are highlighted and the potential applications of cCAFs as novel biomarkers for solid tumor patients discussed.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"127"},"PeriodicalIF":11.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041444","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":"Digital PCR-based genetic profiling from vitreous fluid as liquid biopsy for primary uveal melanoma: a proof-of-concept study.","authors":"R J Nell, M Versluis, N V Menger, M C Gelmi, T H K Vu, R M Verdijk, G P M Luyten, M J Jager, P A van der Velden","doi":"10.1186/s13046-025-03374-y","DOIUrl":"https://doi.org/10.1186/s13046-025-03374-y","url":null,"abstract":"<p><strong>Background: </strong>Uveal melanoma is an aggressive ocular malignancy. Early molecular characterisation of primary tumours is crucial to identify those at risk of metastatic dissemination. Although tumour biopsies are being taken, liquid biopsies of ocular fluids may form a less invasive but relatively unexplored alternative. In this study, we aim to evaluate the DNA content of vitreous fluid from eyes with a uveal melanoma to obtain molecular tumour information.</p><p><strong>Methods: </strong>DNA was isolated from 65 vitreous fluid samples from enucleated eyes with a uveal melanoma and studied using digital PCR. Primary and additional driver mutations (in GNAQ, GNA11, PLCB4, CYSLTR2, BAP1, SF3B1 and EIF1AX) were investigated using accustomed targeted and drop-off assays. The copy numbers of chromosome 3p and 8q were measured using multiplex and single-nucleotide polymorphism-based assays. Our findings were compared to the molecular profile of matched primary tumours and to the clinicopathological tumour characteristics.</p><p><strong>Results: </strong>Almost all (63/65) vitreous fluids had measurable levels of DNA, but melanoma-cell derived DNA (containing the primary driver mutation) was detected in 45/65 samples (median proportion 15.5%, range 0.03-94.4%) and was associated with a larger tumour prominence, but not with any of the molecular tumour subtypes. Among the vitreous fluids with melanoma-cell derived DNA, not all samples harboured (analysable) other mutations or had sufficient statistical power to measure copy numbers. Still, additional mutations in BAP1, SF3B1 and EIF1AX were detected in 15/17 samples and chromosome 3p and 8q copy numbers matched the primary tumour in 19/21 and 18/20 samples, respectively. Collectively, a clinically-relevant molecular classification of the primary tumour could be inferred from 29/65 vitreous fluids.</p><p><strong>Conclusions: </strong>This proof-of-concept study shows that substantial amounts of DNA could be detected in vitreous fluids from uveal melanoma patients, including melanoma-cell derived DNA in 69% of the samples. Prognostically-relevant genetic alterations of the primary tumour could be identified in 45% of the patients. A follow-up study is needed to evaluate our approach in a prospective clinical context. Additionally, our work highlights improved possibilities to sensitively analyse scarce and heterogeneous tumour biopsies, with potential application in other malignancies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"124"},"PeriodicalIF":11.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006069","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":"The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse.","authors":"Catharina Muylaert, Lien Ann Van Hemelrijck, Arne Van der Vreken, Robbe Heestermans, Hatice Satilmis, Emma Verheye, Elina Alaterre, Catharina Olsen, Nathan De Beule, Kim De Veirman, Eline Menu, Karin Vanderkerken, Jérôme Moreaux, Elke De Bruyne","doi":"10.1186/s13046-025-03382-y","DOIUrl":"https://doi.org/10.1186/s13046-025-03382-y","url":null,"abstract":"<p><strong>Background: </strong>The plasma cell malignancy multiple myeloma (MM) remains incurable due to the inevitable development of drug resistance (DR). Epigenetic modifiers are frequently mutated or deregulated in MM patients, contributing to MM progression and relapse. Overexpression of the de novo DNA methyltransferase 3B (DNMT3B) in MM has been reported, correlating with poor prognosis. However, its exact role in MM cell biology and relapse remains elusive.</p><p><strong>Methods: </strong>To evaluate the basal expression and prognostic value of DNMT3B mRNA in terms of overall survival the publicly available gene expression profiling datasets GSE2658, GSE9782, GSE4581, E-MTAB-372, E-TABM-1088 and E-TABM-937 were used. Both the DNMT3B selective inhibitor Nanaomycin A and genetic knockdown using a doxycycline inducible shRNA against DNMT3B were used to target DNMT3B. Viability and apoptosis were assessed using respectively a CellTiter-Glo assay and AnnexinV/7AAD stainings. Cell proliferation was measured by BrdU incorporation and cell cycle analysis, while the clonogenic capacity was evaluated by a colony formation assay. Finally, RNA-seq was performed upon genetic knockdown.</p><p><strong>Results: </strong>Here, we show that DNMT3B is significantly increased in the relapsed setting and high DNMT3B levels are strongly correlating with disease progression and high-risk disease, irrespective of the treatment. Targeting DNMT3B using either genetic inhibition or the selective inhibitor Nanaomycin A strongly impaired MM cell growth, survival and clonogenicity. Moreover, Nanaomycin A reduced viability of primary MM cells from newly diagnosed and relapsed patients. Mechanistic studies revealed that DNMT3B inhibition mainly affects cell cycle and stemness-related transcriptional programs. Notably, DNMT3B depletion affected the stability of the master cell cycle regulator MYC, thereby reducing c-MYC levels and cell viability both in parental and c-MYC overexpressing cells. Finally, Nanaomycin A (re)sensitized MM cells to bortezomib, melphalan and anti-CD38 monoclonal antibodies (daratumumab, isatuximab).</p><p><strong>Conclusion: </strong>Collectively, our findings uncover DNMT3B as a targetable vulnerability in high-risk patients with high DNMT3B/MYC levels.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"125"},"PeriodicalIF":11.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052127","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":"Correction: The anti-tumor efficacy of CDK4/6 Inhibition is enhanced by the combination with PI3K/AKT/mTOR inhibitors through impairment of glucose metabolism in TNBC cells.","authors":"Daniele Cretella, Andrea Ravelli, Claudia Fumarola, Silvia La Monica, Graziana Digiacomo, Andrea Cavazzoni, Roberta Alfieri, Alessandra Biondi, Daniele Generali, Mara Bonelli, Pier Giorgio Petronini","doi":"10.1186/s13046-025-03383-x","DOIUrl":"https://doi.org/10.1186/s13046-025-03383-x","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"122"},"PeriodicalIF":11.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056651","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}