Cellular Oncology最新文献

{"title":"The MEK5/ERK5 pathway promotes the activation of the Hedgehog/GLI signaling in melanoma cells.","authors":"Ignazia Tusa, Sinforosa Gagliardi, Alessio Menconi, Luisa Maresca, Alessandro Tubita, Matteo Lulli, Barbara Stecca, Elisabetta Rovida","doi":"10.1007/s13402-025-01050-z","DOIUrl":"https://doi.org/10.1007/s13402-025-01050-z","url":null,"abstract":"<p><strong>Purpose: </strong>Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We reported that both Hedgehog-GLI (HH/GLI) and Mitogen-activated protein Kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5) pathways promote melanoma growth, and that ERK5 activation is required for HH/GLI-dependent melanoma cell proliferation. Here, we explored whether ERK5 regulates HH/GLI signaling.</p><p><strong>Methods: </strong>Both genetic (using ERK5-specific shRNA) and pharmacologic (using the ERK5 inhibitors JWG-071 and AX15836, and the MAPK/ERK kinase 5, MEK5 inhibitors GW284543 and BIX02189) targeting approaches were used. Luciferase assay using the GLI-binding site luciferase reporter was performed to evaluate GLI transcriptional activity. A constitutively active form of MEK5 (MEK5DD) was used to induce ERK5 activation. 3D spheroid assays were performed in melanoma cells.</p><p><strong>Results: </strong>Genetic and pharmacologic ERK5 inhibition reduces GLI1 and GLI2 protein levels and transcriptional activity of endogenous HH/GLI pathway induced by the agonist SAG in NIH/3T3 cells. In these cells, MEK5DD overexpression potentiates transcriptional activity of endogenous HH/GLI pathway induced by SAG, whereas ERK5 silencing prevents this effect. Consistently, MEK5DD overexpression increases GLI1 and GLI2 protein levels. In melanoma cells, ERK5 silencing reduces GLI1 and GLI2 mRNA and protein levels and inhibits GLI transcriptional activity. MEK5DD further increases the transcriptional activity of the HH/GLI pathway and GLI1 protein levels. Combination of GLI and MEK5 inhibitors is more effective than single treatments in reducing melanoma spheroid growth.</p><p><strong>Conclusions: </strong>MEK5-ERK5 is an activator of GLI transcription factors, and combined targeting of these pathways warrants further preclinical investigation as a potential innovative therapeutic approach for melanoma.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494382","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":"Tumor-infiltrating myeloid cells; mechanisms, functional significance, and targeting in cancer therapy.","authors":"Fatemeh Sadat Toghraie, Maryam Bayat, Mahsa Sadat Hosseini, Amin Ramezani","doi":"10.1007/s13402-025-01051-y","DOIUrl":"https://doi.org/10.1007/s13402-025-01051-y","url":null,"abstract":"<p><p>Tumor-infiltrating myeloid cells (TIMs), which encompass tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs), are of great importance in tumor microenvironment (TME) and are integral to both pro- and anti-tumor immunity. Nevertheless, the phenotypic heterogeneity and functional plasticity of TIMs have posed challenges in fully understanding their complexity roles within the TME. Emerging evidence suggested that the presence of TIMs is frequently linked to prevention of cancer treatment and improvement of patient outcomes and survival. Given their pivotal function in the TME, TIMs have recently been recognized as critical targets for therapeutic approaches aimed at augmenting immunostimulatory myeloid cell populations while depleting or modifying those that are immunosuppressive. This review will explore the important properties of TIMs related to immunity, angiogenesis, and metastasis. We will also document the latest therapeutic strategies targeting TIMs in preclinical and clinical settings. Our objective is to illustrate the potential of TIMs as immunological targets that may improve the outcomes of existing cancer treatments.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494448","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":"Meningeal leukaemic aggregates as foci of cell expansion and chemoresistance in acute lymphoblastic leukaemia metastasis.","authors":"Paula Ortiz-Sánchez, Sara González-Soto, Luz H Villamizar, Jaris Valencia, Eva Jiménez, Rosa Sacedón, Manuel Ramírez, Isabel Fariñas, Alberto Varas, Lidia M Fernández-Sevilla, Ángeles Vicente","doi":"10.1007/s13402-025-01043-y","DOIUrl":"https://doi.org/10.1007/s13402-025-01043-y","url":null,"abstract":"<p><strong>Purpose: </strong>Central nervous system (CNS) involvement and/or relapse remains one of the most important causes of morbidity/mortality in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients. To identify novel therapeutic targets and develop less aggressive therapies, a better understanding of the cellular and molecular microenvironment in leptomeningeal metastases is key. Here, we aimed to investigate the formation of metastatic leptomeningeal aggregates and their relevance to the expansion, survival and chemoresistance acquisition of leukaemia cells.</p><p><strong>Methods: </strong>We used BCP-ALL xenograft mouse models, combined with immunohistofluorescence and flow cytometry, to study the development of CNS metastasis and the contribution of leptomeningeal cells to the organisation of leukaemic aggregates. To in vitro mimic the CNS metastasis, we established co-cultures of three-dimensional (3D) ALL cell spheroids and human leptomeningeal cells (hLMCs) and studied the effects on gene expression, proliferation, cytokine production, and chemoresistance.</p><p><strong>Results: </strong>In xenografted mice, ALL cells infiltrated the CNS at an early stage and, after crossing an ER-TR7⁺ fibroblast-like meningeal cell layer, they proliferated extensively and formed large vascularised leukaemic aggregates supported by a network of podoplanin⁺ leptomeningeal cells. In leukaemia spheroid-hLMC co-cultures, unlike conventional 2D co-cultures, meningeal cells strongly promoted the proliferation of leukaemic cells and generated a pro-inflammatory microenvironment. Furthermore, in 3D cell aggregates, leukaemic cells also developed chemoresistance, at least in part due to ABC transporter up-regulation.</p><p><strong>Conclusion: </strong>Our results provide evidence for the formation of metastatic ALL-leptomeningeal cell aggregates, their pro-inflammatory profile and their contribution to leukaemic cell expansion, survival and chemoresistance in the CNS.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400453","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":"Pathways and outputs orchestrated in tumor microenvironment cells by hypoxia-induced tumor-derived exosomes in pan-cancer.","authors":"Ozel Capik, Omer Faruk Karatas","doi":"10.1007/s13402-025-01042-z","DOIUrl":"https://doi.org/10.1007/s13402-025-01042-z","url":null,"abstract":"<p><p>Hypoxia is a critical microenvironmental condition that plays a major role in driving tumorigenesis and cancer progression. Increasing evidence has revealed novel functions of hypoxia in intercellular communication. The hypoxia induced tumor derived exosomes (hiTDExs) released in high quantities by tumor cells under hypoxia are packed with unique cargoes that are essential for cancer cells' interactions within their microenvironment. These hiTDExs facilitate not only immune evasion but also promote cancer cell growth, survival, angiogenesis, EMT, resistance to therapy, and the metastatic spread of the disease. Nevertheless, direct interventions targeting hypoxia signaling in cancer therapy face challenges related to tumor progression and resistance, limiting their clinical effectiveness. Therefore, deepening our understanding of the molecular processes through which hiTDExs remodels tumors and their microenvironment, as well as how tumor cells adjust to hypoxic conditions, remains essential. This knowledge will pave the way for novel approaches in treating hypoxic tumors. In this review, we discuss recent work revealing the hiTDExs mediated interactions between tumor and its microenvironment. We have described key hiTDExs cargos (lncRNA, circRNAs, cytokines, etc.) and their targets in the receipt cells, responsible for various biological effects. Moreover, we emphasized the importance of hiTDExs as versatile elements of cell communication in the tumor microenvironment. Finally, we highlighted the effects of hiTDExs on the molecular changes in target cells by executing molecular cargo transfer between cells and altering signaling pathways. Currently, hiTDExs show promise in the treatment of diseases. Understanding the molecular processes through which hiTDExs influence tumor behavior and their microenvironment, along with how tumor cells adapt to and survive in low-oxygen conditions, remains a central focus in cancer research, paving the way for innovative strategies in treating hypoxic tumors and enhancing immunotherapy.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383891","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":"Predicting the early therapeutic response to hepatic artery infusion chemotherapy in patients with unresectable HCC using a contrast-enhanced computed tomography-based habitat radiomics model: a multi-center retrospective study.","authors":"Mingsong Wu, Zenglong Que, Shujie Lai, Guanhui Li, Jie Long, Yuqin He, Shunan Wang, Hao Wu, Nan You, Xiang Lan, Liangzhi Wen","doi":"10.1007/s13402-025-01041-0","DOIUrl":"https://doi.org/10.1007/s13402-025-01041-0","url":null,"abstract":"<p><strong>Objective: </strong>Predicting the therapeutic response before initiation of hepatic artery infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) remains challenging for patients with unresectable hepatocellular carcinoma (HCC). Herein, we investigated the potential of a contrast-enhanced CT-based habitat radiomics model as a novel approach for predicting the early therapeutic response to HAIC-FOLFOX in patients with unresectable HCC.</p><p><strong>Methods: </strong>A total of 148 patients with unresectable HCC who received HAIC-FOLFOX combined with targeted therapy or immunotherapy at three tertiary care medical centers were enrolled retrospectively. Tumor habitat features were extracted from subregion radiomics based on CECT at different phases using k-means clustering. Logistic regression was used to construct the model. This CECT-based habitat radiomics model was verified by bootstrapping and compared with a model based on clinical variables. Model performance was evaluated using the area under the curve (AUC) and a calibration curve.</p><p><strong>Results: </strong>Three intratumoral habitats with high, moderate, and low enhancement were identified to construct a habitat radiomics model for therapeutic response prediction. Patients with a greater proportion of high-enhancement intratumoral habitat showed better therapeutic responses. The AUC of the habitat radiomics model was 0.857 (95% CI: 0.798-0.916), and the bootstrap-corrected concordance index was 0.842 (95% CI: 0.785-0.907), resulting in a better predictive value than the clinical variable-based model, which had an AUC of 0.757 (95% CI: 0.679-0.834).</p><p><strong>Conclusion: </strong>The CECT-based habitat radiomics model is an effective, visualized, and noninvasive tool for predicting the early therapeutic response of patients with unresectable HCC to HAIC-FOLFOX treatment and could guide clinical management and decision-making.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191102","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":"LPA released from dying cancer cells after chemotherapy inactivates Hippo signaling and promotes pancreatic cancer cell repopulation.","authors":"Yuzhi Liu, Jie Ding, Shumin Li, Anyi Jiang, Zhiqin Chen, Ming Quan","doi":"10.1007/s13402-025-01038-9","DOIUrl":"10.1007/s13402-025-01038-9","url":null,"abstract":"<p><strong>Purpose: </strong>The Hippo pathway in the tumorigenesis and progression of PDAC, with lysophosphatidic acid (LPA) regulating the Hippo pathway to facilitate cancer progression. However, the impact of the Hippo signaling pathway on tumor repopulation in PDAC remains unreported.</p><p><strong>Methods: </strong>Direct and indirect co-culture models to investigate gemcitabine-induced apoptotic cells can facilitate the repopulation of residual tumor cells. Mass spectrometry analysis was conducted to assess the impact of gemcitabine treatment on the lipid metabolism of pancreatic cancer cells. ELISA assays confirmed gemcitabine promotes the release of LPA from apoptotic pancreatic cancer cells. The expression of Yes-associated protein 1 (YAP1) elucidated the underlying mechanism by which dying cells induce tumor repopulation using qRT-PCR and Western blot. We studied the biological function of pancreatic cancer cells using CCK-8, colony formation, and transwell invasion assays in vitro. Co-culture models were used to validate the impact of Hippo pathway on tumor repopulation, while flow cytometry was employed to assess the sensitivity of pancreatic cancer cells to gemcitabine in the context of Hippo pathway.</p><p><strong>Results: </strong>Gemcitabine-induced dying cells released LPA in a dose-dependent manner, which promoted the proliferation, clonal formation, and invasion of pancreatic cancer cells. Mechanistic studies showed that gemcitabine and LPA facilitated the translocation of YAP1 and induced the inactivation of the Hippo pathway. YAP1 overexpression significantly enhanced the activity of autotaxin, leading to stimulated pancreatic cancer cells to secrete LPA. This mechanism orchestrated a self-sustaining LPA-Hippo feedback loop, which drove the repopulation of residual tumor cells. Simultaneously, it was observed that suppressing LPA and YAP1 expression enhanced the sensitivity of pancreatic cancer cells to gemcitabine.</p><p><strong>Conclusion: </strong>Our investigation indicated that targeting the LPA-YAP1 signaling pathway could serve as a promising strategy to augment the overall therapeutic efficacy against PDAC.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191100","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":"Comprehensive multiomics analysis of the signatures of gastric mucosal bacteria and plasma metabolites across different stomach microhabitats in the development of gastric cancer.","authors":"Bingsen Wang, Jiahui Luan, Weidong Zhao, Junbao Yu, Anqing Li, Xinxin Li, Xiaoqin Zhong, Hongyun Cao, Ruicai Wang, Bo Liu, Shiyong Lu, Mei Shi","doi":"10.1007/s13402-024-00965-3","DOIUrl":"10.1007/s13402-024-00965-3","url":null,"abstract":"<p><strong>Purpose: </strong>As an important component of the microenvironment, the gastric microbiota and its metabolites are associated with tumour occurrence, progression, and metastasis. However, the relationship between the gastric microbiota and the development of gastric cancer is unclear. The present study investigated the role of the gastric mucosa microbiome and metabolites as aetiological factors in gastric carcinogenesis.</p><p><strong>Methods: </strong>Gastric biopsies from different stomach microhabitats (n = 70) were subjected to 16S rRNA gene sequencing, and blood samples (n = 95) were subjected to untargeted metabolome (gas chromatography‒mass spectrometry, GC‒MS) analyses. The datasets were analysed using various bioinformatics approaches.</p><p><strong>Results: </strong>The microbiota diversity and community composition markedly changed during gastric carcinogenesis. High Helicobacter. pylori colonization modified the overall diversity and composition of the microbiota associated with gastritis and cancer in the stomach. Most importantly, analysis of the functional features of the microbiota revealed that nitrate reductase genes were significantly enriched in the tumoral microbiota, while urease-producing genes were significantly enriched in the microbiota of H. pylori-positive patients. A panel of 81 metabolites was constructed to discriminate gastric cancer patients from gastritis patients, and a panel of 15 metabolites was constructed to discriminate H. pylori-positive patients from H. pylori-negative patients. receiver operator characteristic (ROC) curve analysis identified a series of gastric microbes and plasma metabolites as potential biomarkers of gastric cancer.</p><p><strong>Conclusion: </strong>The present study identified a series of signatures that may play important roles in gastric carcinogenesis and have the potential to be used as biomarkers for diagnosis and for the surveillance of gastric cancer patients with minimal invasiveness.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"139-159"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499417","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":"A systematic review on the culture methods and applications of 3D tumoroids for cancer research and personalized medicine.","authors":"Jessica Kalla, Janette Pfneissl, Theresia Mair, Loan Tran, Gerda Egger","doi":"10.1007/s13402-024-00960-8","DOIUrl":"10.1007/s13402-024-00960-8","url":null,"abstract":"<p><p>Cancer is a highly heterogeneous disease, and thus treatment responses vary greatly between patients. To improve therapy efficacy and outcome for cancer patients, more representative and patient-specific preclinical models are needed. Organoids and tumoroids are 3D cell culture models that typically retain the genetic and epigenetic characteristics, as well as the morphology, of their tissue of origin. Thus, they can be used to understand the underlying mechanisms of cancer initiation, progression, and metastasis in a more physiological setting. Additionally, co-culture methods of tumoroids and cancer-associated cells can help to understand the interplay between a tumor and its tumor microenvironment. In recent years, tumoroids have already helped to refine treatments and to identify new targets for cancer therapy. Advanced culturing systems such as chip-based fluidic devices and bioprinting methods in combination with tumoroids have been used for high-throughput applications for personalized medicine. Even though organoid and tumoroid models are complex in vitro systems, validation of results in vivo is still the common practice. Here, we describe how both animal- and human-derived tumoroids have helped to identify novel vulnerabilities for cancer treatment in recent years, and how they are currently used for precision medicine.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1-26"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161474","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":"Telomere transcripts act as tumor suppressor and are associated with favorable prognosis in colorectal cancer with low proliferating cell nuclear antigen expression.","authors":"Philip Kienzl, Abigail J Deloria, Monika Hunjadi, Juliane M Hadolt, Max-Felix Haering, Angrit Bothien, Doris Mejri, Medina Korkut-Demirbaş, Sandra Sampl, Gerhard Weber, Christine Pirker, Severin Laengle, Tamara Braunschmid, Eleni Dragona, Brigitte Marian, Sarantis Gagos, Lingeng Lu, Jeremy D Henson, Loretta M S Lau, Roger R Reddel, Wolfgang Mikulits, Stefan Stättner, Klaus Holzmann","doi":"10.1007/s13402-024-00986-y","DOIUrl":"10.1007/s13402-024-00986-y","url":null,"abstract":"<p><p>Telomeric repeat-containing RNAs (TERRA) and telomerase RNA component (TERC) regulate telomerase activity (TA) and thereby contribute to telomere homeostasis by influencing telomere length (TL) and the cell immortality hallmark of cancer cells. Additionally, the non-canonical functions of telomerase reverse transcriptase (TERT) and TERRA appear to be involved in the epithelial-mesenchymal transition (EMT), which is important for cancer progression. However, the relationship between TERRA and patient prognosis has not been fully characterized. In this small-scale study, 68 patients with colorectal cancer (CRC) were evaluated for correlations between telomere biology, proliferation, and EMT gene transcripts and disease outcome. The proliferating cell nuclear antigen (PCNA) and the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) showed a positive correlation with TERRA, while TA and TERRA exhibited an inverse correlation. Consistent with previous findings, the present study revealed higher expression levels of TERT and TERC, and increased TA and TL in CRC tumor tissue compared to adjacent non-tumor tissue. In contrast, lower expression levels of TERRA were observed in tumor tissue. Patients with high TERRA expression and low PCNA levels exhibited favorable overall survival rates compared to individuals with the inverse pattern. Furthermore, TERRA suppressed CRC tumor growth in severe combined immunodeficiency disease (SCID) mice. In conclusion, our study extends previously published research on TERRA suggesting its potential therapeutic role in telomerase-positive CRC.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"239-247"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113993","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":"ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity.","authors":"Irene Zamora, Mirian Gutiérrez, Alex Pascual, María J Pajares, Miguel Barajas, Lillian M Perez, Sungyong You, Beatrice S Knudsen, Michael R Freeman, Ignacio J Encío, Mirja Rotinen","doi":"10.1007/s13402-024-00957-3","DOIUrl":"10.1007/s13402-024-00957-3","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC.</p><p><strong>Methods: </strong>We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo.</p><p><strong>Results: </strong>OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors.</p><p><strong>Conclusions: </strong>The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"83-99"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181411","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}