Molecular Cancer Research最新文献

{"title":"Oncogenic KRAS Mutations Confer a Unique Mechanotransduction Response to Peristalsis in Colorectal Cancer Cells.","authors":"Abigail J Clevenger, Claudia A Collier, John Paul M Gorley, Sarah Colijn, Maygan K McFarlin, Spencer C Solberg, Scott Kopetz, Amber N Stratman, Shreya A Raghavan","doi":"10.1158/1541-7786.MCR-24-0624","DOIUrl":"10.1158/1541-7786.MCR-24-0624","url":null,"abstract":"<p><p>Colorectal cancer tumors start as polyps on the inner lining of the colorectum, in which they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select colorectal cancer lines that harbored an oncogenic mutation in the Kirsten rat sarcoma virus (KRAS) gene. In this study, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in colorectal cancer. Peristalsis enriched cancer stem cell marker Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) in KRAS mutant lines in a Wnt ligand-independent manner. Conversely, LGR5 enrichment in wild-type KRAS lines exposed to peristalsis were minimal. LGR5 enrichment downstream of peristalsis translated to increased tumorigenicity in vivo. Differences in mechanotransduction were apparent via unbiased gene set enrichment analysis, in which many unique pathways were enriched in wild-type versus mutant lines. Peristalsis also triggered β-catenin nuclear localization independent of Wnt ligands, particularly in KRAS mutant lines. The involvement of KRAS was validated via gain and loss of function strategies. Peristalsis-induced β-catenin activation and LGR5 enrichment depended on the activation of the MEK/ERK cascade. Taken together, our results demonstrated that oncogenic KRAS mutations conferred a unique peristalsis-associated mechanotransduction response to colorectal cancer cells, resulting in cancer stem cell enrichment and increased tumorigenicity. These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS. Implications: Oncogenic KRAS empowers colorectal cancer cells to harness the mechanics of colonic peristalsis for malignant gain independent of other cooperating signals.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"128-142"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562464","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":"Intra- and Extrahepatic Cholangiocarcinomas Display Differing Sensitivities to NK Cell Lysis and Modulate NK Cell Function through Shared and Distinct Pathways.","authors":"Ngan Nguyen, Ian C Henrich","doi":"10.1158/1541-7786.MCR-24-0299","DOIUrl":"10.1158/1541-7786.MCR-24-0299","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is a rare cancer that arises from the bile duct and is broadly classified by the location of the tumor as either intrahepatic cholangiocarcinoma (iCCA) or extrahepatic cholangiocarcinoma (eCCA). Immunotherapy has revolutionized cancer treatment, yet its utility in CCA has been limited as the tumor microenvironment (TME) in CCA is poorly understood compared with other common cancers. Utilizing previously published transcriptome data, our reanalysis has revealed that CCA has one of the highest relative levels of NK cells, a potent cytotoxic immune cell, compared with other cancers. However, despite iCCA and eCCA having comparable relative levels of NK infiltration, NK cell infiltration only correlated with survival in patients with eCCA. Our subsequent investigation revealed that although iCCA and eCCA profoundly altered NK activity, eCCA had a significantly reduced impact on NK functionality. Whereas iCCA was resistant to long-term NK coculture, eCCA was markedly more sensitive. Moreover, although both iCCA and eCCA dysregulated key NK-activating receptors, eCCA coculture did not impact NKp30 nor NKp44 expression. Furthermore, tumor transcriptome analysis of NKHigh CCA samples revealed a modulation of multiple immune and nonimmune cell types within the TME. Implications: These studies are the first to investigate how iCCA and eCCA impact NK cell functionality through shared and distinct mechanisms and how elevated NK cell infiltration could shape the CCA TME in a subtype-dependent manner.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"155-168"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470750","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":"Genome Instability Precedes Viral Integration in Human Papillomavirus-Transformed Tonsillar Keratinocytes.","authors":"Kimberly Chan, Christopher Tseng, Emily Milarachi, David Goldrich, Lisa Schneper, Kathryn Sheldon, Cesar Aliaga, Samina Alam, Sreejata Chatterjee, Karam El-Bayoumy, Craig Meyers, David Goldenberg, James R Broach","doi":"10.1158/1541-7786.MCR-24-0604","DOIUrl":"10.1158/1541-7786.MCR-24-0604","url":null,"abstract":"<p><p>Approximately 70% of oropharyngeal squamous carcinomas (OPSCC) are associated with human papillomavirus (HPV). Although patients with HPV-positive (HPV+) tumors generally have better outcomes than those with HPV-negative tumors, a subset of HPV+ positive patients do have poor outcomes. Our previous work suggested that tumors with integrated virus exhibit significantly greater genome-wide genomic instability than those with only episomal viral genomes, and patients with HPV+ OPSCC with episomal viral genomes had better outcomes. To explore the causal relation between viral integration and genomic instability, we have examined the time course of viral integration and genetic instability in tonsillar keratinocytes transformed with HPV16. HPV-infected human tonsil keratinocyte cell lines were continuously passaged, and every fifth passage, some cells were retained for genomic analysis. Whole-genome sequencing and optical genomic mapping confirmed that virus integrated in five of six cell lines while remaining episomal in the sixth. In all lines, genome instability occurred during early passages but essentially ceased following viral integration; however, it continued to occur in later passages in the episomal line. To test tumorigenicity of the cell lines, cells were injected subcutaneously into the flanks of nude mice. A cell line with the integrated virus induced tumors following injection in the nude mouse whereas that with the episomal virus did not. Implications: Genomic instability in HPV OPSCC tumors is not the result of viral integration but likely promotes integration. Moreover, transformants with episomal virus seem to be less tumorigenic than those with integrated virus.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"119-127"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546520","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":"PRMT5 Maintains Tumor Stem Cells to Promote Pediatric High-Grade Glioma Tumorigenesis.","authors":"John DeSisto, Ilango Balakrishnan, Aaron J Knox, Gabrielle Link, Sujatha Venkataraman, Rajeev Vibhakar, Adam L Green","doi":"10.1158/1541-7786.MCR-24-0233","DOIUrl":"10.1158/1541-7786.MCR-24-0233","url":null,"abstract":"<p><p>Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated central nervous system tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a knockdown (KD) screen for epigenetic regulators, we identified PRMT5 as essential for PHGG cell growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor-initiating cells essential for tumor growth. We conducted in vitro analyses, including limiting dilution studies of self-renewal, to determine the phenotypic effects of PRMT5 KD. We performed chromatin immunoprecipitation sequencing (ChIP-Seq) to identify PRMT5-mediated epigenetic changes and performed gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histologic characteristics resulting from PRMT5 KD or administration of a PRMT5 inhibitor ± radiation therapy. In vitro, PRMT5 KD slowed cell-cycle progression, tumor growth and self-renewal, and altered chromatin occupancy at genes associated with differentiation, tumor formation, and growth. In vivo, PRMT5 KD increased survival and reduced tumor aggressiveness; however, pharmacologic inhibition of PRMT5 with or without radiation therapy did not improve survival. PRMT5 KD epigenetically reduced tumor-initiating cells' self-renewal, leading to increased survival in preclinical models. Pharmacologic inhibition of PRMT5 enzymatic activity may have failed in vivo due to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that nonenzymatic activities of PRMT5 are more relevant. Implications: PRMT5 maintains and promotes the growth of stem-like cells that initiate and drive tumorigenesis in PHGG.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"107-118"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470763","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":"ASAP1 and ARF1 Regulate Myogenic Differentiation in Rhabdomyosarcoma by Modulating TAZ Activity.","authors":"Katie E Hebron, Olivia L Perkins, Angela Kim, Xiaoying Jian, Sofia A Girald-Berlingeri, Haiyan Lei, Jack F Shern, Elizabeth A Conner, Paul A Randazzo, Marielle E Yohe","doi":"10.1158/1541-7786.MCR-24-0490","DOIUrl":"10.1158/1541-7786.MCR-24-0490","url":null,"abstract":"<p><p>Despite aggressive, multimodal therapies, the prognosis of patients with refractory or recurrent rhabdomyosarcoma (RMS) has not improved in four decades. Because RMS resembles skeletal muscle precursor cells, differentiation-inducing therapy has been proposed for patients with advanced disease. In RAS-mutant PAX fusion-negative RMS (FN-RMS) preclinical models, MEK1/2 inhibition (MEKi) induces differentiation, slows tumor growth, and extends survival. However, the response is short-lived. A better understanding of the molecular mechanisms regulating FN-RMS differentiation could improve differentiation therapy. In this study, we identified a role in FN-RMS differentiation for ASAP1, an ADP ribosylation factor (ARF) GTPase-activating protein (GAP) with both proinvasive and tumor-suppressor functions. We found that ASAP1 knockdown inhibited differentiation in FN-RMS cells. Interestingly, knockdown of the GTPases ARF1 or ARF5, targets of ASAP1 GAP activity, also blocked differentiation of FN-RMS. We discovered that loss of ARF pathway components blocked myogenic transcription factor expression. Therefore, we examined the effects on transcriptional regulators. MEKi led to the phosphorylation and inactivation of WW domain-containing transcriptional regulator 1 (WWTR1; TAZ), a homolog of the pro-proliferative transcriptional co-activator YAP1, regulated by the Hippo pathway. However, loss of ASAP1 or ARF1 blocked this inactivation, which inhibits MEKi-induced differentiation. Finally, MEKi-induced differentiation was rescued by dual knockdown of ASAP1 and WWTR1. This study shows that ASAP1 and ARF1 are necessary for myogenic differentiation, providing a deeper understanding of differentiation in FN-RMS and illuminating an opportunity to advance differentiation therapy. Implications: ASAP1 and ARF1 regulate MEKi-induced differentiation of FN-RMS cells by modulating WWTR1 (TAZ) activity, supporting YAP1/TAZ inhibition as a FN-RMS differentiation therapy strategy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"95-106"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569322","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":"Loss of PI5P4Kα Slows the Progression of a Pten Mutant Basal Cell Model of Prostate Cancer.","authors":"Joanna Triscott, Marika Lehner, Andrej Benjak, Matthias Reist, Brooke M Emerling, Charlotte K Y Ng, Simone de Brot, Mark A Rubin","doi":"10.1158/1541-7786.MCR-24-0290","DOIUrl":"10.1158/1541-7786.MCR-24-0290","url":null,"abstract":"<p><p>Although early prostate cancer depends on the androgen receptor signaling pathway, which is predominant in luminal cells, there is much to be understood about the contribution of epithelial basal cells in cancer progression. Herein, we observe cell type-specific differences in the importance of the metabolic enzyme phosphatidylinositol 5-phosphate 4-kinase alpha (PI5P4Kα; gene name PIP4K2A) in the prostate epithelium. We report the development of a basal cell-specific genetically engineered mouse model targeting Pip4k2a alone or in combination with the tumor suppressor phosphatase and tensin homolog (Pten). PI5P4Kα is enriched in basal cells, and no major histopathologic changes were detectable following gene deletion. Notably, the combined loss of Pip4k2a slowed the development of Pten mutant mouse prostatic intraepithelial neoplasia. Through the inclusion of a lineage tracing reporter, we utilize single-cell RNA sequencing to evaluate changes resulting from in vivo downregulation of Pip4k2a and characterize cell populations influenced in the established Probasin-Cre- and cytokeratin 5-Cre-driven genetically engineered mouse model. Transcriptomic pathway analysis points toward the disruption of lipid metabolism as a mechanism for reduced tumor progression. This was functionally supported by shifts of carnitine lipids in LNCaP prostate cancer cells treated with siPIP4K2A. Overall, these data nominate PI5P4Kα as a target for PTEN mutant prostate cancer. Implications: PI5P4Kα is enriched in prostate basal cells, and its targeted loss slows the progression of a model of advanced prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"33-45"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392035","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":"N-Linked Fucosylated Glycans Are Biomarkers for Prostate Cancer with a Neuroendocrine and Metastatic Phenotype.","authors":"Joseph E Ippolito, Jordan P Hartig, Kaitlyn Bejar, Hani Nakhoul, Jennifer K Sehn, Cody Weimholt, Grace Grimsley, Elena Nunez, Nikolaos A Trikalinos, Deyali Chatterjee, Eric H Kim, Anand S Mehta, Peggi M Angel, Dean A Troyer, Robin J Leach, Eva Corey, Jennifer D Wu, Richard R Drake","doi":"10.1158/1541-7786.MCR-24-0660","DOIUrl":"10.1158/1541-7786.MCR-24-0660","url":null,"abstract":"<p><p>Prostate cancer is a heterogeneous disease with a spectrum of pathology and outcomes ranging from indolent to lethal. Although there have been recent advancements in prognostic tissue biomarkers, limitations still exist. We leveraged matrix-assisted laser desorption/ionization imaging of formalin-fixed, paraffin embedded prostate cancer specimens to determine if N-linked glycans expressed in the extracellular matrix of lethal neuroendocrine prostate cancer were also expressed in conventional prostate adenocarcinomas that were associated with poor outcomes. We found that N-glycan fucosylation was abundant in neuroendocrine prostate cancer as well as adenocarcinomas at the time of prostatectomy that eventually developed recurrent metastatic disease. Analysis of patient-derived xenografts revealed that this fucosylation signature was enriched differently across metastatic disease organ sites, with the highest abundance in liver metastases. These data suggest that N-linked fucosylated glycans could be an early tissue biomarker for poor prostate cancer outcomes. Implications: These studies identify that hyper-fucosylated N-linked glycans are enriched in neuroendocrine prostate cancer and conventional prostate adenocarcinomas that progress to metastatic disease, thus advancing biomarker discovery and providing insights into mechanisms underlying metastatic disease.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"59-70"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470762","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 Distinct Roles of NEIL1 and XPA in Limiting Aflatoxin B1-Induced Mutagenesis in Mice.","authors":"Michael M Luzadder, Irina G Minko, Vladimir L Vartanian, Marten Davenport, Lev M Fedorov, Amanda K McCullough, R Stephen Lloyd","doi":"10.1158/1541-7786.MCR-24-0577","DOIUrl":"10.1158/1541-7786.MCR-24-0577","url":null,"abstract":"<p><p>Dietary exposure to aflatoxin B1 (AFB1) is a risk factor for the development of hepatocellular carcinomas. Following metabolic activation, AFB1 reacts with guanines to form covalent DNA adducts, which induce high-frequency G > T transversions. The molecular signature associated with these mutational events aligns with the single-base substitution signature 24 (SBS24) in the Catalog of Somatic Mutations in Cancer database. Deficiencies in either base excision repair due to the absence of Nei-like DNA glycosylase 1 (NEIL1) or nucleotide excision repair due to the absence of xeroderma complementation group A protein (XPA) contribute to hepatocellular carcinomas in murine models. In the current study, ultra-low error duplex sequencing was used to characterize mutational profiles in liver DNAs of NEIL1-deficient, XPA-deficient, and DNA repair-proficient mice following neonatal injection of 1 mg/kg AFB1. Analyses of AFB1-induced mutations showed high cosine similarity to SBS24 regardless of repair proficiency status. The absence of NEIL1 resulted in an approximately 30% increase in the frequency of mutations, with the distribution suggesting preferential NEIL1-dependent repair of AFB1 lesions in open chromatin regions. A trend of increased mutagenesis was also observed in the absence of XPA. Consistent with the role of XPA in transcription-coupled repair, mutational profiles in XPA-deficient mice showed disruption of the transcriptional bias in mutations associated with SBS24. Implications: Our findings define the roles of DNA repair pathways in AFB1-induced mutagenesis and carcinogenesis in murine models, with these findings having implications in human health for those with base excision repair and nucleotide excision repair deficiencies.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"46-58"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470764","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":"Gram-Negative Microflora Dysbiosis Facilitates Tumor Progression and Immune Evasion by Activating the CCL3/CCL5-CCR1-MAPK-PD-L1 Pathway in Esophageal Squamous Cell Carcinoma.","authors":"Huiqin Yang, Jiahao Cai, Xiaolong Huang, Cheng Zhan, Chunlai Lu, Jie Gu, Teng Ma, Hongyu Zhang, Tao Cheng, Fengkai Xu, Di Ge","doi":"10.1158/1541-7786.MCR-24-0451","DOIUrl":"10.1158/1541-7786.MCR-24-0451","url":null,"abstract":"<p><p>Gram-negative (G-) microflora dysbiosis occurs in multiple digestive tumors and is found to be the dominant microflora in the esophageal squamous cell carcinoma (ESCC) microenvironment. The continuous stimulation of G- bacterium metabolites may cause tumorigenesis and reshape the microimmune environment in ESCC. However, the mechanism of G- bacilli causing immune evasion in ESCC remains underexplored. We identified CC chemokine receptor 1 (CCR1) as a tumor-indicating gene in ESCC. Interestingly, expression levels of CCR1 and PD-L1 were mutually upregulated after G- bacilli metabolite lipopolysaccharide stimulation. First, we found that CCR1 high expression levels were associated with poor overall survival in ESCC. Importantly, we found that high levels of CCR1 expression upregulated PD-L1 expression by activating MAPK phosphorylation in ESCC and induced tumor malignant behavior. Finally, we found that T-cell exhaustion and cytotoxicity suppression were associated with CCR1 expression in ESCC, which were decreased after CCR1 inhibiting. Our work identifies CCR1 as a potential immune check point regulator of PD-L1 and may cause T-cell exhaustion and cytotoxicity suppression in ESCC microenvironment and highlights the potential value of CCR1 as a therapeutic target of immunotherapy. Implications: The esophageal microbial environment and its metabolites significantly affect the outcome of immunotherapy for ESCC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"71-85"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350768","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":"B-type Plexins Regulate Mitosis via RanGTPase.","authors":"Nicholus Mukhwana, Ritu Garg, Abul Azad, Alexandria R Mitchell, Magali Williamson","doi":"10.1158/1541-7786.MCR-23-0836","DOIUrl":"10.1158/1541-7786.MCR-23-0836","url":null,"abstract":"<p><p>Aberrant mitosis can result in aneuploidy and cancer. The small GTPase, Ras-related nuclear protein (Ran), is a key regulator of mitosis. B-type plexins regulate Ran activity by acting as RanGTPase-activating proteins 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 Plexin B1 functions in the control of mitosis. Depletion of Plexin B1 affects mitotic spindle assembly, significantly delaying anaphase. This leads to mitotic catastrophe in some cells and prolonged application of the spindle assembly checkpoint. Plexin B1 depletion also promoted acentrosomal microtubule nucleation and defects in spindle pole refocusing 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 Plexin B1 depletion. Plexin B1 localizes to the mitotic spindle in dividing cells. The mitotic defects observed upon Plexin B1 depletion were rescued by an RCC1 inhibitor, indicating that Plexin B1 signals, via Ran, to affect mitosis. These errors in mitosis generated multinucleate cells and nuclei of altered morphology and abnormal karyotype. Furthermore, semaphorin 4D 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.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"8-19"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","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}