Molecular Cancer Research最新文献_第2页

Crizotinib Enhances PARP Inhibitor Efficacy in Ovarian Cancer Cells and Xenograft Models by Inducing Autophagy. 克唑替尼通过诱导自噬增强 PARP 抑制剂对卵巢癌细胞和异种移植模型的疗效。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-09-04 DOI: 10.1158/1541-7786.MCR-23-0680

Janice M Santiago-O'Farrill, Alicia Blessing Bollu, Hailing Yang, Vivian Orellana, Marc Pina, Xudong Zhang, Jinsong Liu, Robert C Bast, Zhen Lu

{"title":"Crizotinib Enhances PARP Inhibitor Efficacy in Ovarian Cancer Cells and Xenograft Models by Inducing Autophagy.","authors":"Janice M Santiago-O'Farrill, Alicia Blessing Bollu, Hailing Yang, Vivian Orellana, Marc Pina, Xudong Zhang, Jinsong Liu, Robert C Bast, Zhen Lu","doi":"10.1158/1541-7786.MCR-23-0680","DOIUrl":"10.1158/1541-7786.MCR-23-0680","url":null,"abstract":"Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and clonogenic growth in two-olaparib resistant cell lines. More importantly, this effect was consistently observed in patient-derived organoids. Furthermore, combined treatment with crizotinib and olaparib led to tumor regression in human ovarian xenograft models. Mechanistically, the combination resulted in increased levels of reactive oxygen species (ROS), induced DNA damage, and decreased the phosphorylation of AKT, mTOR, and ULK-1, contributing to increased olaparib-induced autophagy and apoptosis. Notably, pharmacologic, or genetic inhibition or autophagy reduced the sensitivity of ovarian cancer cell lines to olaparib and crizotinib treatment, underscoring the role of autophagy in cell death. Blocking ROS mitigated olaparib/crizotinib-induced autophagy and cell death while restoring levels of phosphorylated AKT, mTOR and ULK-1. These findings suggest that crizotinib can improve the therapeutic efficacy of olaparib by enhancing autophagy. Implications: The combination of crizotinib and PARPi presents a promising strategy, that could provide a novel approach to enhance outcomes for patients with ovarian cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081932","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}

引用次数: 0

USP44 Overexpression Drives a MYC-Like Gene Expression Program in Neuroblastoma through Epigenetic Reprogramming. USP44 过表达通过表观遗传重编程驱动神经母细胞瘤中的 MYC 类基因表达程序。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-09-04 DOI: 10.1158/1541-7786.MCR-23-0454

Thomas L Ekstrom, Sajjad Hussain, Tibor Bedekovics, Asma Ali, Lucia Paolini, Hina Mahmood, Raya M Rosok, Jan Koster, Steven A Johnsen, Paul J Galardy

{"title":"USP44 Overexpression Drives a MYC-Like Gene Expression Program in Neuroblastoma through Epigenetic Reprogramming.","authors":"Thomas L Ekstrom, Sajjad Hussain, Tibor Bedekovics, Asma Ali, Lucia Paolini, Hina Mahmood, Raya M Rosok, Jan Koster, Steven A Johnsen, Paul J Galardy","doi":"10.1158/1541-7786.MCR-23-0454","DOIUrl":"10.1158/1541-7786.MCR-23-0454","url":null,"abstract":"Neuroblastoma is an embryonic cancer that contributes disproportionately to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer, although epigenetic pathways have been implicated in disease pathogenesis. We used an expression-based computational screen that examined the impact of deubiquitinating enzymes on patient survival to identify potential new targets. We identified the histone H2B deubiquitinating enzyme USP44 as the enzyme with the greatest impact on survival in patients with neuroblastoma. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN amplification. The subset of patients with tumors expressing high levels of USP44 had significantly worse survival, including those with tumors lacking MYCN amplification. We showed experimentally that USP44 regulates neuroblastoma cell proliferation, migration, invasion, and neuronal development. Depletion of the histone H2B ubiquitin ligase subunit RNF20 resulted in similar findings, strongly implicating this histone mark as the target of USP44 activity in this disease. Integration of transcriptome and epigenome in analyses demonstrates a distinct set of genes that are regulated by USP44, including those in Hallmark MYC target genes in both murine embryonic fibroblasts and the SH-SY5Y neuroblastoma cell line. We conclude that USP44 is a novel epigenetic regulator that promotes aggressive features and may be a novel target in neuroblastoma. Implications: This study identifies a new genetic marker of aggressive neuroblastoma and identifies the mechanisms by which its overactivity contributes to the pathophysiology of this disease.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075056","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}

引用次数: 0

miR-497 Target Gene Regulatory Network in Angiosarcoma. 血管肉瘤中的 miR-497 靶基因调控网络

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-09-04 DOI: 10.1158/1541-7786.MCR-23-1075

Annaleigh Benton, Noah M Moriarty, Emma Terwilliger, Bozhi Liu, Ant Murphy, Hannah Maluvac, Mae Shu, Lauren E Gartenhaus, Nimod D Janson, Claire M Pfeffer, Sagar M Utturkar, Elizabeth I Parkinson, Nadia A Lanman, Jason A Hanna

{"title":"miR-497 Target Gene Regulatory Network in Angiosarcoma.","authors":"Annaleigh Benton, Noah M Moriarty, Emma Terwilliger, Bozhi Liu, Ant Murphy, Hannah Maluvac, Mae Shu, Lauren E Gartenhaus, Nimod D Janson, Claire M Pfeffer, Sagar M Utturkar, Elizabeth I Parkinson, Nadia A Lanman, Jason A Hanna","doi":"10.1158/1541-7786.MCR-23-1075","DOIUrl":"10.1158/1541-7786.MCR-23-1075","url":null,"abstract":"Angiosarcoma is a vascular sarcoma that is highly aggressive and metastatic. Because of its rarity, treatment options for patients are limited. Therefore, more research is needed to identify possible therapeutic vulnerabilities. We previously found that conditional deletion of Dicer1 drives angiosarcoma development in mice. Given the role of DICER1 in canonical miRNA biogenesis, this suggests that miRNA loss is important in angiosarcoma development. After testing miRNAs previously suggested to have a tumor-suppressive role in angiosarcoma, miRNA-497-5p (miR-497) suppressed cell viability most significantly. We also found that miR-497 overexpression led to significantly reduced cell migration and tumor formation. To understand the mechanism of miR-497 in tumor suppression, we identified clinically relevant target genes using a combination of RNA-sequencing data in an angiosarcoma cell line, expression data from patients with angiosarcoma, and target prediction algorithms. We validated miR-497 direct regulation of cyclin-D2, cyclin-dependent kinase 6, and vesicle amine transport protein 1 (VAT1). One of these genes, VAT1, is an understudied protein that has been suggested to promote cell migration and metastasis in other cancers. Indeed, we find that pharmacologic inhibition of VAT1 with the natural product neocarzilin A reduces angiosarcoma migration. Implications: This work supports the potent tumor-suppressive abilities of miR-497 in angiosarcoma, providing evidence for its potential as a therapeutic agent, and provides insight into the mechanisms of tumor suppression through analysis of the target gene regulatory network of miR-497.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071305","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}

引用次数: 0

Mechanisms of Glioblastoma Replication: Ca2+ Flares and Cl- Currents. 胶质母细胞瘤的复制机制：Ca2+耀斑和Cl-电流

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-09-04 DOI: 10.1158/1541-7786.MCR-23-0934

Yunzhen Li, Cesar Adolfo Sanchez Triviño, Andres Hernandez, Simone Mortal, Federica Spada, Ilona Krivosheia, Nicoletta Franco, Renza Spelat, Daniela Cesselli, Ivana Manini, Miran Skrap, Anna Menini, Fabrizia Cesca, Vincent Torre

{"title":"Mechanisms of Glioblastoma Replication: Ca2+ Flares and Cl- Currents.","authors":"Yunzhen Li, Cesar Adolfo Sanchez Triviño, Andres Hernandez, Simone Mortal, Federica Spada, Ilona Krivosheia, Nicoletta Franco, Renza Spelat, Daniela Cesselli, Ivana Manini, Miran Skrap, Anna Menini, Fabrizia Cesca, Vincent Torre","doi":"10.1158/1541-7786.MCR-23-0934","DOIUrl":"10.1158/1541-7786.MCR-23-0934","url":null,"abstract":"Glioblastoma (GBM) is amongst the deadliest types of cancers, with no resolutive cure currently available. GBM cell proliferation in the patient's brain is a complex phenomenon controlled by multiple mechanisms. The aim of this study was to determine whether the ionic fluxes controlling cell duplication could represent a target for GBM therapy. In this work, we combined multi-channel Ca2+ and Cl- imaging, optical tweezers, electrophysiology, and immunohistochemistry to describe the role of ion fluxes in mediating the cell volume changes that accompany mitosis of U87 GBM cells. We identified three main steps: (i) in round GBM cells undergoing mitosis, during the transition from anaphase to telophase and cytokinesis, large Ca2+ flares occur, reaching values of 0.5 to 1 μmol/L; (ii) these Ca2+ flares activate Ca2+-dependent Cl- channels, allowing the entry of Cl- ions; and (iii) to maintain osmotic balance, GBM cells swell to complete mitosis. This sequence of steps was validated by electrophysiological experiments showing that Cl- channels are activated either directly or indirectly by Ca2+, and by additional live-cell imaging experiments. Cl- channel blockers with different molecular structures, such as niflumic acid and carbenoxolone, blocked GBM replication by arresting GBM cells in a round configuration. These results describe the central role of Ca2+ flares and Cl- fluxes during mitosis and show that inhibition of Ca2+-activated Cl- channels blocks GBM replication, opening the way to new approaches for the clinical treatment of GBM. Implications: Our work identifies ionic fluxes occurring during cell division as targets for devising novel therapies for glioblastoma treatment.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184475","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}

引用次数: 0

Small Cell Lung Cancer Neuronal Features and Their Implications for Tumor Progression, Metastasis, and Therapy. 小细胞肺癌神经元特征及其对肿瘤进展、转移和治疗的影响。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-09-04 DOI: 10.1158/1541-7786.MCR-24-0265

Griffin G Hartmann, Julien Sage

{"title":"Small Cell Lung Cancer Neuronal Features and Their Implications for Tumor Progression, Metastasis, and Therapy.","authors":"Griffin G Hartmann, Julien Sage","doi":"10.1158/1541-7786.MCR-24-0265","DOIUrl":"10.1158/1541-7786.MCR-24-0265","url":null,"abstract":"Small cell lung cancer (SCLC) is an epithelial neuroendocrine form of lung cancer for which survival rates remain dismal and new therapeutic approaches are greatly needed. Key biological features of SCLC tumors include fast growth and widespread metastasis, as well as rapid resistance to treatment. Similar to pulmonary neuroendocrine cells, SCLC cells have traits of both hormone-producing cells and neurons. In this study, we specifically discuss the neuronal features of SCLC. We consider how neuronal G protein-coupled receptors and other neuronal molecules on the surface of SCLC cells can contribute to the growth of SCLC tumors and serve as therapeutic targets in SCLC. We also review recent evidence for the role of neuronal programs expressed by SCLC cells in the fast proliferation, migration, and metastasis of these cells. We further highlight how these neuronal programs may be particularly relevant for the development of brain metastases and how they can assist SCLC cells to functionally interact with neurons and astrocytes. A greater understanding of the molecular and cellular neuronal features of SCLC is likely to uncover new vulnerabilities in SCLC cells, which may help develop novel therapeutic approaches. More generally, the epithelial-to-neuronal transition observed during tumor progression in SCLC and other cancer types can contribute significantly to tumor development and response to therapy.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443119","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}

引用次数: 0

Hepatitis B Virus X Protein Represses Expression of Tumor Suppressor PTPN18 in Hepatocellular Carcinoma. 乙型肝炎病毒 X 蛋白抑制肝细胞癌中肿瘤抑制因子 PTPN18 的表达

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-09-04 DOI: 10.1158/1541-7786.MCR-23-0696

Zhenyu Zhou, Wei Yu, Huoming Li, Juanyi Shi, Shiyu Meng, Yongcong Yan, Ruibin Chen, Haohan Liu, Jie Wang, Jian Sun, Zhiyu Xiao, Jianlong Zhang

{"title":"Hepatitis B Virus X Protein Represses Expression of Tumor Suppressor PTPN18 in Hepatocellular Carcinoma.","authors":"Zhenyu Zhou, Wei Yu, Huoming Li, Juanyi Shi, Shiyu Meng, Yongcong Yan, Ruibin Chen, Haohan Liu, Jie Wang, Jian Sun, Zhiyu Xiao, Jianlong Zhang","doi":"10.1158/1541-7786.MCR-23-0696","DOIUrl":"10.1158/1541-7786.MCR-23-0696","url":null,"abstract":"HBV-associated hepatocellular carcinoma (HCC) represents the prevalent form of HCC, with HBx protein being a crucial oncoprotein. Numerous members of the protein tyrosine phosphatase nonreceptor (PTPN) family have been confirmed to be significantly associated with the occurrence and progression of malignant tumors. Our group previously identified the involvement of PTPN13 in HCC. However, the roles of other PTPNs in HCC require further investigation. In this study, we found that PTPN18 expression was significantly downregulated within HCC tissues compared with adjacent nontumor and reference liver tissues. Functionally, PTPN18 exerted inhibitory effects on the proliferation, migration, invasion, and sphere-forming capability of HCC cells while concurrently promoting apoptotic processes. Through phospho-protein microarray screening followed by subsequent validation experiments, we identified that PTPN18 could activate the p53 signaling pathway and suppress the AKT/FOXO1 signaling cascade in HCC cells. Moreover, the HBx protein mediated the repression of PTPN18 expression by upregulating miR-128-3p. Collectively, our study unveiled the role of PTPN18 as a tumor suppressor in HBV-related HCC. Implications: Our findings revealed that PTPN18 might be a potential diagnostic and therapeutic target for HBV-related HCC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087774","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}

引用次数: 0

Clinically Relevant Humanized Mouse Models of Metastatic Prostate Cancer Facilitate Therapeutic Evaluation. 与临床相关的转移性前列腺癌人源化小鼠模型有助于进行治疗评估。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-09-04 DOI: 10.1158/1541-7786.MCR-23-0904

Raymond J Kostlan, John T Phoenix, Audris Budreika, Marina G Ferrari, Neetika Khurana, Jae E Choi, Kristin Juckette, Somnath Mahapatra, Brooke L McCollum, Russell Moskal, Rahul Mannan, Yuanyuan Qiao, Donald J Vander Griend, Arul M Chinnaiyan, Steven Kregel

{"title":"Clinically Relevant Humanized Mouse Models of Metastatic Prostate Cancer Facilitate Therapeutic Evaluation.","authors":"Raymond J Kostlan, John T Phoenix, Audris Budreika, Marina G Ferrari, Neetika Khurana, Jae E Choi, Kristin Juckette, Somnath Mahapatra, Brooke L McCollum, Russell Moskal, Rahul Mannan, Yuanyuan Qiao, Donald J Vander Griend, Arul M Chinnaiyan, Steven Kregel","doi":"10.1158/1541-7786.MCR-23-0904","DOIUrl":"10.1158/1541-7786.MCR-23-0904","url":null,"abstract":"There is tremendous need for improved prostate cancer models. Anatomically and developmentally, the mouse prostate differs from the human prostate and does not form tumors spontaneously. Genetically engineered mouse models lack the heterogeneity of human cancer and rarely establish metastatic growth. Human xenografts are an alternative but must rely on an immunocompromised host. Therefore, we generated prostate cancer murine xenograft models with an intact human immune system (huNOG and huNOG-EXL mice) to test whether humanizing tumor-immune interactions would improve modeling of metastatic prostate cancer and the impact of androgen receptor-targeted and immunotherapies. These mice maintain multiple human immune cell lineages, including functional human T-cells and myeloid cells. Implications: To the best of our knowledge, results illustrate the first model of human prostate cancer that has an intact human immune system, metastasizes to clinically relevant locations, responds appropriately to standard-of-care hormonal therapies, and can model both an immunosuppressive and checkpoint-inhibition responsive immune microenvironment.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184473","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}

引用次数: 0

EHMT1/2 inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner. EHMT1/2抑制以CD8 T细胞依赖的方式促进耐药卵巢癌肿瘤的消退。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-08-13 DOI: 10.1158/1541-7786.MCR-24-0067

Lily L Nguyen, Zachary L Watson, Raquel Ortega, Elizabeth R Woodruff, Kimberly R Jordan, Ritsuko Iwanaga, Tomomi M Yamamoto, Courtney A Bailey, Francis To, Shujian Lin, Fabian R Villagomez, Abigail D Jeong, Saketh R Guntupalli, Kian Behbakht, Veronica Gibaja, Nausica Arnoult, Edward B Chuong, Benjamin G Bitler

{"title":"EHMT1/2 inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner.","authors":"Lily L Nguyen, Zachary L Watson, Raquel Ortega, Elizabeth R Woodruff, Kimberly R Jordan, Ritsuko Iwanaga, Tomomi M Yamamoto, Courtney A Bailey, Francis To, Shujian Lin, Fabian R Villagomez, Abigail D Jeong, Saketh R Guntupalli, Kian Behbakht, Veronica Gibaja, Nausica Arnoult, Edward B Chuong, Benjamin G Bitler","doi":"10.1158/1541-7786.MCR-24-0067","DOIUrl":"10.1158/1541-7786.MCR-24-0067","url":null,"abstract":"Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer. We discovered that inhibition of EHMT1/2 resensitizes cells to PARPi. Markedly, we show that single EHMTi and combinatory EHMTi/PARPi significantly reduced PARPi-resistant tumor burden and that this reduction is partially dependent on CD8 T cells. Altogether, our results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy. Implications: Targeting the epigenome of therapy-resistant ovarian cancer induces an anti-tumor response mediated in part through an anti-tumor immune response.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971525","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}

引用次数: 0

B-type plexins regulate mitosis via RanGTPase. B 型丛集蛋白通过 RanGTPase 调节有丝分裂。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-08-13 DOI: 10.1158/1541-7786.MCR-23-0836

Nicholus Mukhwana, Ritu Garg, Alexandria R Mitchell, Abul Azad, Magali Williamson

{"title":"B-type plexins regulate mitosis via RanGTPase.","authors":"Nicholus Mukhwana, Ritu Garg, Alexandria R Mitchell, Abul Azad, Magali Williamson","doi":"10.1158/1541-7786.MCR-23-0836","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-23-0836","url":null,"abstract":"Aberrant mitosis can result in aneuploidy and cancer. The small GTPase, Ran, is a key regulator of mitosis. B-type Plexins regulate Ran activity by acting as RanGTPase activating proteins (GAPs) and have been implicated in cancer progression. However, whether B-type plexins have a role in mitosis has not so far been investigated. We show here that PlexinB1 functions in the control of mitosis. Depletion of PlexinB1 affects mitotic spindle assembly, significantly delaying anaphase. This leads to mitotic catastrophe in some cells, and prolonged application of the spindle assembly checkpoint. PlexinB1 depletion also promoted acentrosomal microtubule nucleation and defects in spindle pole refocussing and increased the number of cells with multipolar or aberrant mitotic spindles. An increase in lagging chromosomes or chromosomal bridges at anaphase was also found upon PlexinB1 depletion. PlexinB1 localises to the mitotic spindle in dividing cells. The mitotic defects observed upon PlexinB1 depletion were rescued by an RCC1 inhibitor, indicating that PlexinB1 signals, via Ran, to affect mitosis. These errors in mitosis generated multinucleate cells, and nuclei of altered morphology and abnormal karyotype. Furthermore, Semaphorin4D-treatment increased the percentage of cells with micronuclei, precursors of chromothripsis. Implications: Defects in B-type plexins may contribute to the well-established role of plexins in cancer progression by inducing chromosomal instability.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971524","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}

引用次数: 0

TEAD2 Promotes Hepatocellular Carcinoma Development and Sorafenib Resistance via TAK1 Transcriptional Activation. TEAD2 通过 TAK1 转录激活促进肝细胞癌发展和索拉非尼抗性

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-08-06 DOI: 10.1158/1541-7786.MCR-24-0060

Yahui Zhang, Yidan Ren, Guoying Dong, Qinlian Jiao, Nan Guo, Ping Gao, Ya Li, Yunshan Wang, Wei Zhao

{"title":"TEAD2 Promotes Hepatocellular Carcinoma Development and Sorafenib Resistance via TAK1 Transcriptional Activation.","authors":"Yahui Zhang, Yidan Ren, Guoying Dong, Qinlian Jiao, Nan Guo, Ping Gao, Ya Li, Yunshan Wang, Wei Zhao","doi":"10.1158/1541-7786.MCR-24-0060","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0060","url":null,"abstract":"Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer, yet the effectiveness of treatment for HCC patients is significantly hindered by the development of drug resistance to sorafenib. Through the application of ATAC-seq to examine drug-resistant HCC tissues, we identified substantial alterations in chromatin accessibility in sorafenib-resistant patient-derived xenograft (PDX) models. Employing multi-omics data integration analysis, we confirmed TEAD2 as a crucial transcriptional regulator in sorafenib-resistant HCC tissues. Functional assays illustrated that TEAD2 plays a role in promoting HCC progression and enhancing resistance to sorafenib. Mechanistically, we demonstrated that TEAD2 binds to the TAK1 promoter to modulate its expression. Furthermore, we established the involvement of TAK1 in mediating TEAD2-induced sorafenib resistance in HCC, a finding supported by the effectiveness of TAK1 inhibitors. Our research highlights that targeting the TEAD2-TAK1 axis can effectively mitigate drug resistance in HCC patients receiving sorafenib treatment, offering a novel approach for enhancing the treatment outcomes and prognosis of individuals with HCC. Implications: Targeting the TEAD2-TAK1 axis presents a promising therapeutic strategy to overcome sorafenib resistance in HCC, potentially improving treatment outcomes and prognosis for patients.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897896","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}

引用次数: 0