Cellular Oncology最新文献

{"title":"From benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST): a gaming among multiple factors.","authors":"Yanan Yu, Chengjiang Wei, Minghui Yue, Cheng Zhang, Yixiao Wang, Zhichao Wang","doi":"10.1007/s13402-025-01054-9","DOIUrl":"https://doi.org/10.1007/s13402-025-01054-9","url":null,"abstract":"<p><p>Almost all patients of Neurofibromatosis Type I (NF1) develop benign peripheral nerve tumors called neurofibromas, which are derived from neural crest Schwann cell lineage progenitors with biallelic NF1 gene mutations. More than 90% of NF1 patients develop dermal neurofibromas (DN), and 25-50% develop plexiform neurofibromas (PN). In 8-13% of individuals with NF1, PN can transform into malignant peripheral nerve sheath tumors (MPNSTs), a type of nerve soft tissue sarcoma that is the main cause of mortality of NF1 patients. In addition to arising from benign neurofibromas (50%), MPNSTs can also occur spontaneously (~40%) or following radiation therapy (~10%). Treatment for MPNST is limited to complete resection with negative margins. Still, the high recurrence of MPNST is a major concern. However, full resection of the pre-malignant lesions can largely reduce the recurrence and mortality of patients. So, early diagnosis and distinguishing malignancy from benign and premalignant lesions are particularly important. During the progression from benign neurofibromas to malignancy, a variety of changes including tumor morphology, genetic mutations, expression of multiple signaling pathways-related proteins and genome instability gradually occur. In this review, we detail these changes with the goals of identifying the histological and/or molecular signs of malignancy initiation, and an optimal therapeutic intervention window, to inhibit tumor progression and reduce the rate of mortality.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The origin of patient-derived cancer organoids from pathologically undiagnosed specimen in patients with pancreatobiliary cancers.","authors":"Bomi Kim, Jiho Park, Hee Young Na, Sinwoo Park, Jeonghwa Jin, Kwangrok Jung, Jong-Chan Lee, Jin-Hyeok Hwang, Minseok Seo, Jaihwan Kim","doi":"10.1007/s13402-024-01026-5","DOIUrl":"10.1007/s13402-024-01026-5","url":null,"abstract":"<p><strong>Purpose: </strong>Tissue confirmation of pancreatobiliary cancer is often difficult because of the location of the tumor and structure of the surrounding blood vessels. Patient-derived cancer organoids (PDCOs) reflect the genomic characteristics of individual cancers. Although diverse attempts to construct PDCOs for various pancreatobiliary cancer models are ongoing, no research results have yet confirmed the possibility of performing a precise diagnosis on PDCOs derived from pathologically negative patient samples.</p><p><strong>Methods: </strong>We obtained a total of nine samples, including pathologically negative samples, from four patients (three patients with pancreatic cancer and one patient with gallbladder cancer) using different tissue acquisition methods to establish PDCOs (success rate 75%).</p><p><strong>Results: </strong>We successfully verified whether the constructed PDCOs could represent the tissues of patients with pancreatobiliary cancer at each multi-omics level using tumor panel sequencing, single-cell RNA sequencing, hematoxylin and eosin, and immunohistochemical staining. PDCOs from pathologically negative samples showed expression patterns of malignant ductal cell-related biomarkers similar to those of other pathologically positive samples. Furthermore, the expression patterns at the single-cell level in PDCO from patients ultimately diagnosed with gallbladder cancer after surgery were different from those in patients with pancreatic cancer.</p><p><strong>Conclusion: </strong>Therefore, our study implicated the potential of PDCOs as diagnostic and research tools, including for case involving limited tissue samples. Based on these results, we anticipate that this could be extended to more advanced studies, such as drug sensitivity testing, through large-scale trials in the near future.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"523-535"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834052","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":"Retraction Note: TRAIL enhances quinacrine-mediated apoptosis in breast cancer cells through induction of autophagy via modulation of p21 and DR5 interactions.","authors":"Sarita Das, Anmada Nayak, Sumit Siddharth, Deepika Nayak, Satya Narayan, Chanakya Nath Kundu","doi":"10.1007/s13402-025-01045-w","DOIUrl":"10.1007/s13402-025-01045-w","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"537"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADAR1 enhances tumor proliferation and radioresistance in non-small cell lung cancer by interacting with Rad18.","authors":"Chen Tian, Chang Li, Juanjuan Wang, Yuting Liu, Jiaqi Gao, Xiaohua Hong, Feifei Gu, Kai Zhang, Yue Hu, Hongjie Fan, Li Liu, Yulan Zeng","doi":"10.1007/s13402-024-01012-x","DOIUrl":"10.1007/s13402-024-01012-x","url":null,"abstract":"<p><strong>Purpose: </strong>Posttranslational modification significantly contributes to the transcriptional diversity of tumors. Adenosine deaminase acting on RNA 1 (ADAR1) and its mediated adenosine-to-inosine (A-to-I) editing have been reported to influence tumorigenesis across various cancer types. Nevertheless, the relationship between ADAR1 and radioresistence remains to be elucidated.</p><p><strong>Methods: </strong>The protein expression was detected by immunohistochemistry and Western Blot, while the mRNA expression was measured by RT-qPCR. The tumor growth was evaluated by CCK8, colony formation assays, EdU assay, and in-vivo mouse model. γ-H2AX foci formation, neutral comet tailing assay, and clonogenic cell survival assay were performed to determine the DNA damage and radiosensitivity. RNA-seq was conducted to identify the main downstream effector. The interaction between ADAR1 and Rad18 was examined by immunofluorescence and co-immunoprecipitation.</p><p><strong>Results: </strong>We reported that ADAR1 was upregulated and correlated with poor prognosis in non-small cell lung cancer (NSCLC). In addition, we demonstrated that silencing ADAR1 significantly impaired tumor growth and improved tumor sensitivity to radiotherapy in vitro and in vivo. Mechanistically, we found that Rad18, which has been established as a versatile modulator of DNA repair, was the major downstream effector of ADAR1. ADAR1 not only regulated Rad18 mRNA expression by E2F3 but also colocalized and interacted with Rad18. Finally, our rescue experiments demonstrated that ADAR1's protumorigenic functions were partially dependent on Rad18.</p><p><strong>Conclusion: </strong>Our results revealed the role of ADAR1 in cooperation with Rad18 in modulating oncogenesis and radioresistance in NSCLC for the first time, and suggested the therapeutic potential of targeting ADAR1 in overcoming radioresistance.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"471-485"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680410","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":"ALKBH4 functions as a hypoxia-responsive tumor suppressor and inhibits metastasis and tumorigenesis.","authors":"Ji-Lin Chen, Pei-Hua Peng, Han-Tsang Wu, Dar-Ren Chen, Ching-Yun Hsieh, Jeng-Shou Chang, Joseph Lin, Huan-Yu Lin, Kai-Wen Hsu","doi":"10.1007/s13402-024-01004-x","DOIUrl":"10.1007/s13402-024-01004-x","url":null,"abstract":"<p><strong>Purpose: </strong>The human AlkB homolog (ALKBH) dioxygenase superfamily plays a crucial role in gene regulation and is implicated in cancer progression. Under hypoxic conditions, hypoxia-inducible factors (HIFs) dynamically regulate methylation by controlling various dioxygenases, thereby modulating gene expression. However, the role of hypoxia-responsive AlkB dioxygenase remains unclear.</p><p><strong>Methods: </strong>The molecular events were examined using real-time PCR and Western blot analysis. Tumor cell aggressiveness was evaluated through migration, invasion, MTT, trypan blue exclusion, and colony formation assays. In vivo metastatic models and xenograft experiments were conducted to evaluate tumor progression.</p><p><strong>Results: </strong>Here, we examined the expression of the ALKBH superfamily under hypoxic conditions and found that ALKBH4 expression was negatively regulated by hypoxia. Knockdown of ALKBH4 enhanced the epithelial-mesenchymal transition (EMT), cell migration, invasion, and growth in vitro. The silencing of ALKBH4 enhanced metastatic ability and tumor growth in vivo. Conversely, overexpression of ALLKBH4 reversed these observations. Furthermore, overexpression of ALKBH4 significantly reversed hypoxia/HIF-1α-induced EMT, cell migration, invasion, tumor metastasis, and tumorigenicity. Notably, high expression of ALKBH4 was associated with better outcomes in head and neck cancer and breast cancer patients. Enrichment analysis also revealed that ALKBH4 was negatively enriched in hypoxia-related pathways. Clinically, a negative correlation between ALKBH4 and HIF-1α protein expression has been observed in tissues from both head and neck cancers and breast cancers.</p><p><strong>Conclusion: </strong>These findings collectively suggest that ALKBH4 acts as a tumor suppressor and holds therapeutic potential for hypoxic tumors.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"425-435"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459010","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 long non-coding RNA NEAT1 contributes to aberrant STAT3 signaling in pancreatic cancer and is regulated by a metalloprotease-disintegrin ADAM8/miR-181a-5p axis.","authors":"Yutong Gao, Kimia Zandieh, Kai Zhao, Natalia Khizanishvili, Pietro Di Fazio, Xiangdi Yu, Leon Schulte, Michelle Aillaud, Ho-Ryun Chung, Zachary Ball, Marion Meixner, Uta-Maria Bauer, Detlef Klaus Bartsch, Malte Buchholz, Matthias Lauth, Christopher Nimsky, Lena Cook, Jörg W Bartsch","doi":"10.1007/s13402-024-01001-0","DOIUrl":"10.1007/s13402-024-01001-0","url":null,"abstract":"<p><strong>Purpose: </strong>Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and several studies demonstrate that STAT3 has critical roles throughout the course of PDAC pathogenesis.</p><p><strong>Methods: </strong>TCGA, microarray, and immunohistochemistry data from a PDAC cohort were used for clinical analyses. Panc89 cells with ADAM8 knockout, re-expression of ADAM8 mutants, and Panc1 cells overexpressing ADAM8 were generated. Gene expression analyses of ADAM8, STAT3, long non-coding (lnc) RNA NEAT1, miR-181a-5p and ICAM1 were performed by quantitative PCR. Subcellular fractionation quantified NEAT1 expression in cytoplasm and nucleus of PDAC cell lines. Cell proliferation, scratch, and invasion assays were performed to detect growth rate, migration and invasion capabilities of cells. Gain and loss of function experiments were carried out to investigate the biological effects of lncRNA NEAT1 and miR-181a-5p on PDAC cells and downstream genes. Dual-luciferase reporter gene assay determined interaction and binding sites of miR-181a-5p in lncRNA NEAT1. Pull down assays, RNA binding protein immunoprecipitation (RIP), and ubiquitination assays explored the molecular interaction between lncRNA NEAT1 and STAT3.</p><p><strong>Results: </strong>High ADAM8 expression causes aberrant STAT3 signaling in PDAC cells and is positively correlated with NEAT1 expression. NEAT1 binding to STAT3 was confirmed and prevents STAT3 degradation in the proteasome as increased degradation of STAT3 was observed in ADAM8 knockout cells and cells treated with bortezomib. Furthermore, miRNA-181a-5p regulates NEAT1 expression by direct binding to the NEAT1 promoter.</p><p><strong>Conclusion: </strong>ADAM8 regulates intracellular STAT3 levels via miR-181a-5p and NEAT1 in pancreatic cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"391-409"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459016","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":"BCAT1 contributes to the development of TKI-resistant CML.","authors":"Yu Jiang, Difan Zhang, Xiaoxiao He, Chiqi Chen, Li Xie, Ligen Liu, Zhuo Yu, Yaping Zhang, Junke Zheng, Dan Huang","doi":"10.1007/s13402-024-01003-y","DOIUrl":"10.1007/s13402-024-01003-y","url":null,"abstract":"<p><strong>Purpose: </strong>Although most of chronic myeloid leukemia (CML) patients can be effectively treated by the tyrosine kinase inhibitors (TKIs), such as Imatinib, TKI-resistance still occurs in approximately 15-17% of cases. Although many studies indicate that branched chain amino acid (BCAA) metabolism may contribute to the TKI resistance in CML, the detailed mechanisms remains largely unknown.</p><p><strong>Method: </strong>The cell proliferation, colony formation and in vivo transplantation were used to determined the functions of BCAT1 in leukemogenesis. Quantitative real-time PCR (RT-PCR), western blotting, RNA sequencing, BCAA stimulation in vitro were applied to characterize the underlying molecular mechanism that control the leukemogenic activity of BCAT1-knockdown cells.</p><p><strong>Results: </strong>In this report, we revealed that branched chain amino acid transaminase 1 (BCAT1) is highly enriched in both mouse and human TKI-resistant CML cells. Leukemia was almost completely abrogated upon BCAT1 knockdown during transplantation in a BCR-ABL^T315I-induced murine TKI-resistant CML model. Moreover, knockdown of BCAT1 led to a dramatic decrease in the proliferation of TKI-resistant human leukemia cell lines. BCAA/BCAT1 signaling enhanced the phosphorylation of CREB, which is required for maintenance of TKI-resistant CML cells. Importantly, blockade of BCAA/BCAT1 signaling efficiently inhibited leukemogenesis both in vivo and in vitro.</p><p><strong>Conclusions: </strong>These findings demonstrate the role of BCAA/BCAT1 signaling in cancer development and suggest that targeting BCAA/BCAT1 signaling is a potential strategy for interfering with TKI-resistant CML.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"411-424"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459011","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":"Cell death in glioblastoma and the central nervous system.","authors":"Kyle Malone, Eric LaCasse, Shawn T Beug","doi":"10.1007/s13402-024-01007-8","DOIUrl":"10.1007/s13402-024-01007-8","url":null,"abstract":"<p><p>Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"313-349"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582175","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":"Targeting the Notch-Furin axis with 2-hydroxyoleic acid: a key mechanism in glioblastoma therapy.","authors":"Raquel Rodríguez-Lorca, Ramón Román, Roberto Beteta-Göbel, Manuel Torres, Victoria Lladó, Pablo V Escribá, Paula Fernández-García","doi":"10.1007/s13402-024-00995-x","DOIUrl":"10.1007/s13402-024-00995-x","url":null,"abstract":"<p><strong>Purpose: </strong>Glioblastomas (GBMs) are highly treatment-resistant and aggressive brain tumors. 2OHOA, which is currently running a phase IIB/III clinical trial for newly diagnosed GBM patients, was developed in the context of melitherapy. This therapy focuses on the regulation of the membrane's structure and organization with the consequent modulation of certain cell signals to revert the pathological state in several disorders. Notch signaling has been associated with tumorigenesis and cell survival, potentially driving the pathogenesis of GBM. The current study aims to determine whether 2OHOA modulates the Notch pathway as part of its antitumoral mechanism.</p><p><strong>Methods: </strong>2OHOA's effect was evaluated on different components of the pathway by Western blot, Q-PCR, and confocal microscopy. Notch receptor processing was analyzed by subcellular fractionation and colocalization studies. Furin activity was evaluated under cleavage of its substrate by fluorescence assays and its binding affinity to 2OHOA was determined by surface plasmon resonance.</p><p><strong>Results: </strong>We found that 2OHOA inhibits Notch2 and Notch3 signaling by dual mechanism. Notch2 inhibition is unleashed by impairment of its processing through the inactivation of furin activity by physical association. Instead, Notch3 is transcriptionally downregulated leading to a lower activation of the pathway. Moreover, we also found that HES1 overexpression highlighted the relevance of this pathway in the 2OHOA pharmacological efficacy.</p><p><strong>Conclusion: </strong>These findings report that the inhibition of Notch signaling by 2OHOA plays a role in its anti-tumoral activity, an effect that may be driven through direct inhibition of furin, characterizing a novel target of this bioactive lipid to treat GBM.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"373-390"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459015","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":"SUMOylation regulates the aggressiveness of breast cancer-associated fibroblasts.","authors":"Angelica Martínez-López, Guiomar Infante, Marina Mendiburu-Eliçabe, Andrés Machuca, Olga M Antón, Mónica González-Fernández, José L Luque-García, Robert B Clarke, Sonia Castillo-Lluva","doi":"10.1007/s13402-024-01005-w","DOIUrl":"10.1007/s13402-024-01005-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cancer-associated fibroblasts (CAFs) are the most abundant stromal cellular component in the tumor microenvironment (TME). CAFs contribute to tumorigenesis and have been proposed as targets for anticancer therapies. Similarly, dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to tumorigenesis and drug resistance in various cancers, including breast cancer. We explored the role of SUMOylation in breast CAFs and evaluated its potential as a therapeutic strategy in breast cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We used pharmacological and genetic approaches to analyse the functional crosstalk between breast tumor cells and CAFs. We treated breast CAFs with the SUMO1 inhibitor ginkgolic acid (GA) at two different concentrations and conditioned media was used to analyse the proliferation, migration, and invasion of breast cancer cells from different molecular subtypes. Additionally, we performed quantitative proteomics (SILAC) to study the differential signalling pathways expressed in CAFs treated with low or high concentrations of GA. We confirmed these results both in vitro and in vivo. Moreover, we used samples from metastatic breast cancer patients to evaluate the use of GA as a therapeutic strategy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Inhibition of SUMOylation with ginkgolic acid (GA) induces death in breast cancer cells but does not affect the viability of CAFs, indicating that CAFs are resistant to this therapy. While CAF viability is unaffected, CAF-conditioned media (CM) is altered by GA, impacting tumor cell behaviour in different ways depending on the overall degree to which SUMO1-SUMOylated proteins are dysregulated. Breast cancer cell lines exhibited a concentration-dependent response to conditioned media (CM) from CAFs. At a low concentration of GA (10 µM), there was an increase in proliferation, migration and invasion of breast cancer cells. However, at a higher concentration of GA (30 µM), these processes were inhibited. Similarly, analysis of tumor development revealed that at 10 µM of GA, the tumors were heavier and there was a greater degree of metastasis compared to the tumors treated with the higher concentration of GA (30 µM). Moreover, some of these effects could be explained by an alteration in the activity of the GTPase Rac1 and the activation of the AKT signalling pathway. The results obtained using SILAC suggest that different concentrations of GA affected cellular processes differentially, possibly influencing the secretome of CAFs. Treatment of metastatic breast cancer with GA demonstrated the use of SUMOylation inhibition as an alternative therapeutic strategy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The study highlights the importance of SUMOylation in the tumor microenvironment, specifically in cancer-associated fibroblasts (CAFs). Targeting SUMOylation in CAFs affects their signalling pathways and secretome in a concentration-dependent manner, regulat","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"437-453"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459014","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}