Molecular Cancer Research最新文献_第2页

Exploring B7-H4's Role in Prostate Cancer Dormancy after Androgen Deprivation Therapy: Extracellular Matrix Interactions and Therapeutic Opportunities. 探讨B7-H4在前列腺癌雄激素剥夺治疗后休眠中的作用：细胞外基质相互作用和治疗机会。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0958

Ning Kang, Hui Xue, Nelson K Y Wong, Yen-Yi Lin, Adam Classen, Rebecca Wu, Htoo Zarni Oo, Xin Dong, Angela Trinh, Dong Lin, Mads Daugaard, Christopher Ong, Colin Collins, Martin Gleave, Yuzhuo Wang

{"title":"Exploring B7-H4's Role in Prostate Cancer Dormancy after Androgen Deprivation Therapy: Extracellular Matrix Interactions and Therapeutic Opportunities.","authors":"Ning Kang, Hui Xue, Nelson K Y Wong, Yen-Yi Lin, Adam Classen, Rebecca Wu, Htoo Zarni Oo, Xin Dong, Angela Trinh, Dong Lin, Mads Daugaard, Christopher Ong, Colin Collins, Martin Gleave, Yuzhuo Wang","doi":"10.1158/1541-7786.MCR-24-0958","DOIUrl":"10.1158/1541-7786.MCR-24-0958","url":null,"abstract":"Prostate cancer is mainly managed with androgen deprivation therapy (ADT), but this often leads to a dormant state and subsequent relapse as lethal castration-resistant prostate cancer (CRPC). Using our unique prostate cancer patient-derived xenograft dormancy models, we investigated this critical dormant phase and discovered a selective increase in B7-H4 expression during the dormancy period following mouse host castration. This finding is supported by observations in clinical specimens of patients with prostate cancer treated with ADT. Differential expression analyses revealed the enrichment of extracellular matrix (ECM)-cell interaction pathways in B7-H4-positive cells. Functional assays demonstrated a crucial role of B7-H4 in maintaining dormancy within the ECM niche. Specifically, B7-H4 expression in LNCaP cells reduced proliferation within the dormant ECM in vitro and significantly delayed relapse in castrated hosts in vivo. These results shed light on the dynamic regulation of B7-H4 during prostate cancer dormancy and underscore its potential as a therapeutic target for preventing CRPC relapse. Implications: Our study identified membranous B7-H4 expression during ADT-induced dormancy, highlighting its potential as a therapeutic target for managing dormant prostate cancer and preventing fatal CRPC relapse.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"327-338"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951495","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

Bmal1-Mediated Circadian MELK Expression Potentiates MELK Inhibitor Chronotherapy for Esophageal Cancer. bmal1介导的MELK昼夜表达增强了MELK抑制剂对食管癌的时间治疗。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0498

Boning Zeng, Chao Sun, Qian Tang, Nan Li, Siying Chen, Yili Yang, Xiao Wang, Shaoxiang Wang

{"title":"Bmal1-Mediated Circadian MELK Expression Potentiates MELK Inhibitor Chronotherapy for Esophageal Cancer.","authors":"Boning Zeng, Chao Sun, Qian Tang, Nan Li, Siying Chen, Yili Yang, Xiao Wang, Shaoxiang Wang","doi":"10.1158/1541-7786.MCR-24-0498","DOIUrl":"10.1158/1541-7786.MCR-24-0498","url":null,"abstract":"Esophageal squamous cell carcinoma (ESCC) remains a global health challenge. Circadian clock and maternal embryonic leucine zipper kinase (MELK) play a key role in tumorigenesis. However, a link between circadian clock dysregulation and MELK function in the occurrence and development of ESCC remains elusive. Here, In the in vivo and in vitro systems, we found for the first time that MELK exhibits pronounced circadian rhythms expression in mice esophageal tissue, xenograft model, and human ESCC cells. The diurnal differences expression between peak (ZT0) and trough (ZT12) points in normal esophageal tissue is nearly 10-fold. Circadian expression of MELK in ESCC cells was regulated by Bmal1 through binding to the MELK promoter. Supporting this, the levels of MELK were increased significantly in patients with ESCC and were accompanied by altered expression of core clock genes, especially, since Bmal1 is prominently upregulated. Most importantly, Bmal1-deleted eliminated the rhythmic expression of MELK, whereas the knockdown of other core genes had no effect on MELK expression. Furthermore, in nude mice with transplanted tumors, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"288-299"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854491","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

Lysosomal-Mitochondrial Interaction Promotes Tumor Growth in Squamous Cell Carcinoma of the Head and Neck. 溶酶体/线粒体相互作用促进头颈部鳞状细胞癌的肿瘤生长。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0337

Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri

{"title":"Lysosomal-Mitochondrial Interaction Promotes Tumor Growth in Squamous Cell Carcinoma of the Head and Neck.","authors":"Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri","doi":"10.1158/1541-7786.MCR-24-0337","DOIUrl":"10.1158/1541-7786.MCR-24-0337","url":null,"abstract":"Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other [lysosomal-mitochondrial interaction (LMI)] is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas [including squamous cell carcinoma of the head and neck (SCCHN)] overexpress transmembrane member 16A (TMEM16A), a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis; however, its impact on mitochondrial function has not been explored. In this study, we show that in the context of high-TMEM16A SCCHN, (i) patients display increased mitochondrial content, specifically complex I; (ii) in vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (iii) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (iv) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitate a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of LMI may serve as a therapeutic approach for patients with high TMEM16A-expressing SCCHN.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"339-349"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854576","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

Single-cell and spatial transcriptomics reveal a tumor-associated macrophage subpopulation that mediates prostate cancer progression and metastasis.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-19 DOI: 10.1158/1541-7786.MCR-24-0791

Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Yanxin Xu, Ninib Baryawno, Shulin Wu, Chin-Lee Wu, Akash Patnaik, Philip J Saylor, David B Sykes, Douglas M Dahl

{"title":"Single-cell and spatial transcriptomics reveal a tumor-associated macrophage subpopulation that mediates prostate cancer progression and metastasis.","authors":"Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Yanxin Xu, Ninib Baryawno, Shulin Wu, Chin-Lee Wu, Akash Patnaik, Philip J Saylor, David B Sykes, Douglas M Dahl","doi":"10.1158/1541-7786.MCR-24-0791","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0791","url":null,"abstract":"Tumor-associated macrophages (TAMs) are a transcriptionally heterogeneous population, and their abundance and function in prostate cancer is poorly defined. We integrated parallel datasets from single-cell RNA-sequencing, spatial transcriptomics and multiplex immunofluorescence to reveal the dynamics of TAMs in primary and metastatic prostate cancer. Four TAM subpopulations were identified. Notably, one of these TAM subsets was defined by the co-expression of SPP1+ and TREM2+ and was significantly enriched in metastatic tumors. The SPP1+/TREM2+ TAMs were enriched in the metastatic tumor microenvironment in both human patient samples and murine models of prostate cancer. The abundance of these SPP1+/TREM2+ macrophages was associated with patient progression free survival. Spatially, TAMs within prostate cancer bone metastases were highly enriched within the tumor region, consistent with their pro-tumorigenic role. Blocking SPP1 in RM1 prostate cancer mouse model led to improved efficacy of anti-PD-1 treatment, and increased CD8 T cell infiltration in tumor. These findings suggest that targeting SPP1+ TAMs may offer a promising therapeutic strategy and potentially enhance the effects of immune checkpoint inhibition (ICI) in advanced prostate cancer. Implications: This study expands our understanding of the diverse roles of macrophage populations in prostate cancer metastases and highlights new therapeutic targets.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657868","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

Empty spiracles homeobox 2 (EMX2) transcription factor functions as a tumor suppressor in renal cell carcinoma by targeting CADM1. Empty spiracles homeobox 2 (EMX2) 转录因子通过靶向 CADM1 在肾细胞癌中发挥肿瘤抑制因子的功能。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-17 DOI: 10.1158/1541-7786.MCR-24-0496

Zhibin Fu, Wenqi Chen, Di Gu, Juan Li, Kai Dong, Yuying Lan, Tao Liu, Bianhong Zhang, Lei Li, Ethan Lee, Chenghua Yang, Tao P Zhong, Linhui Wang

{"title":"Empty spiracles homeobox 2 (EMX2) transcription factor functions as a tumor suppressor in renal cell carcinoma by targeting CADM1.","authors":"Zhibin Fu, Wenqi Chen, Di Gu, Juan Li, Kai Dong, Yuying Lan, Tao Liu, Bianhong Zhang, Lei Li, Ethan Lee, Chenghua Yang, Tao P Zhong, Linhui Wang","doi":"10.1158/1541-7786.MCR-24-0496","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0496","url":null,"abstract":"Renal cell carcinoma (RCC), a prevalent urinary system malignancy, often metastasizes at an early stage. Characterized by a complex pathogenesis and high mortality rate, RCC poses a significant clinical challenge. We evaluated the expression level of EMX2 in RCC patients and revealed a significant reduction of EMX2 expression, correlating with poor RCC patient prognosis. EMX2 functions as a tumor suppressor and inhibits RCC cell proliferation and migration, accompanied by programmed cell death. Implantation of EMX2-transduced RCC cells beneath the mouse kidney capsule or subcutaneous injection of transduced RCC cells results in a reduction in tumor growth and size. Through RNA-seq and chromatin immunoprecipitation sequencing analyses, we have identified Cell Adhesion Molecule 1 (CADM1) as a direct transcriptional target of EMX2's suppressive effects. CADM1 induction by EMX2 triggers PARP1-mediated parthanatos, a specific type of cell death due to mitochondrial oxidation reduction, in migrating RCC cells. Concurrently, EMX2-CADM1 upregulation instigates Caspase-3-dependent apoptosis in attached RCC cells. Furthermore, EMX2-CADM1 transcriptional axis also inhibits the PI3K-AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by EMX2-CADM1 axis promote RCC cell death and suppresse its growth and invasion, providing potential intervention strategies for combating RCC. Implications: The EMX2-CADM1 transcriptional axis offers a promising therapeutic target for inducing cell death and inhibiting growth and invasion in renal cell carcinoma, which could lead to more effective treatment strategies for this aggressive malignancy.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648176","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

KSR2 promotes self-renewal and clonogenicity of small-cell lung carcinoma.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-10 DOI: 10.1158/1541-7786.MCR-24-0546

Dianna H Huisman, Deepan Chatterjee, Robert A Svoboda, Heidi M Vieira, Abbie S Ireland, Sydney Skupa, James W Askew, Danielle E Frodyma, Luc Girard, Kurt W Fisher, Michael S Kareta, John D Minna, Trudy G Oliver, Robert E Lewis

{"title":"KSR2 promotes self-renewal and clonogenicity of small-cell lung carcinoma.","authors":"Dianna H Huisman, Deepan Chatterjee, Robert A Svoboda, Heidi M Vieira, Abbie S Ireland, Sydney Skupa, James W Askew, Danielle E Frodyma, Luc Girard, Kurt W Fisher, Michael S Kareta, John D Minna, Trudy G Oliver, Robert E Lewis","doi":"10.1158/1541-7786.MCR-24-0546","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0546","url":null,"abstract":"Small-cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells (PNECs) was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony forming ability of tumor propagating cells (TPCs) in vitro and their tumor initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of ASCL1-subtype SCLC tumors, and a potential subtype-specific therapeutic target. Implications: Manipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597417","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

ANGEL2 modulates wildtype TP53 translation and doxorubicin chemosensitivity in colon cancer. ANGEL2 可调节结肠癌中野生型 TP53 的翻译和多柔比星的化学敏感性。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-07 DOI: 10.1158/1541-7786.MCR-24-0702

Christopher August Lucchesi, Saisamkalpa Mantrala, Darren Tran, Neelu Batra, Avani Durve, Conner Suen, Jin Zhang, Paramita Ghosh, Xinbin Chen

{"title":"ANGEL2 modulates wildtype TP53 translation and doxorubicin chemosensitivity in colon cancer.","authors":"Christopher August Lucchesi, Saisamkalpa Mantrala, Darren Tran, Neelu Batra, Avani Durve, Conner Suen, Jin Zhang, Paramita Ghosh, Xinbin Chen","doi":"10.1158/1541-7786.MCR-24-0702","DOIUrl":"10.1158/1541-7786.MCR-24-0702","url":null,"abstract":"Multiple lines of correlative evidence support a role for ANGEL2, a novel cancer-relevant RNA-binding protein, in the modulation of chemoresistance and cancer patient survival. However, to date, no study has determined a mechanism by which ANGEL2 modulates cancer progression, nor its role in chemoresistance. Herein, we demonstrate that loss of ANGEL2 leads to a substantial decrease of the key tumor suppressor protein TP53. We show that ANGEL2 directly interacts with EIF4E, the rate limiting protein in cap-dependent translation. This interaction abrogates the ability for the TP53 translation repressor RBM38 to interact with EIF4E thereby enhancing TP53 translation. Loss of ANGEL2 in cancer cell lines resulted in increased 2D and 3D spheroid cell growth, and resistance to doxorubicin and etoposide. With therapeutic potential, treatment with Pep7, a seven amino-acid peptide derived from ANGEL2, rescued wildtype TP53 expression and sensitized cancer cells to doxorubicin. Together, we conclude that ANGEL2 modulates the EIF4E-RBM38 complex to enhance wildtype TP53 translation, and further, the Pep7 peptide may be explored as a therapeutic strategy for cancers which harbor wildtype TP53 expression. Implications: Loss of ANGEL2 contributes to decreased wildtype TP53 translation promoting doxorubicin resistance which can be rescued via an ANGEL2-derived peptide.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573421","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

Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine Resistant Multiple Myeloma.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-06 DOI: 10.1158/1541-7786.MCR-24-0444

Zachary J Walker, Katherine F Vaeth, Amber Baldwin, Denis J Ohlstrom, Lauren T Reiman, Kady A Dennis, Kate Matlin, Beau M Idler, Brett M Stevens, Neelanjan Mukherjee, Daniel W Sherbenou

{"title":"Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine Resistant Multiple Myeloma.","authors":"Zachary J Walker, Katherine F Vaeth, Amber Baldwin, Denis J Ohlstrom, Lauren T Reiman, Kady A Dennis, Kate Matlin, Beau M Idler, Brett M Stevens, Neelanjan Mukherjee, Daniel W Sherbenou","doi":"10.1158/1541-7786.MCR-24-0444","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0444","url":null,"abstract":"Protein homeostasis is critical to the survival of multiple myeloma (MM) cells. While this is targeted with proteasome inhibitors, mRNA translation inhibition has not entered trials. Recent work illustrates broad sensitivity MM cells to the translation inhibitor omacetaxine. We hypothesized that understanding how MM becomes resistant will lead to the development of drug combinations to prevent or delay relapse. We generated omacetaxine resistance in H929 and MM1S MM cell lines and compared them to parental lines. Resistant lines displayed decreased sensitivity to omacetaxine, with EC50 > 100 nM, compared to parental sensitivity of 24-54 nM. Since omacetaxine inhibits protein synthesis, we performed both RNA-sequencing and ribosome profiling (Ribo-seq) to identify shared and unique regulatory strategies of resistance. Transcripts encoding translation factors and containing Terminal OligoPyrimidine (TOP) sequence in their 5' UTR were translationally upregulated in both resistant cell lines. The mTOR pathway promotes the translation of TOP motif containing mRNAs. Indeed, mTOR inhibition with Torin 1 restored partial sensitivity to omacetaxine in both resistant cell lines. The combination was synergistic in omacetaxine naïve MM cell lines, and a combination effect was observed in vivo. Primary MM cells from patient samples were also sensitive to the combination. These results provide a rational approach for omacetaxine-based combination in patients with multiple myeloma, which have historically shown better responses to multi-agent regimens. Implications: Through the use of ribosome profiling, our findings indicate mTOR inhibition as a novel combination therapy for partnering with the translation inhibitor omacetaxine in the treatment of multiple myeloma.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567016","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

Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-06 DOI: 10.1158/1541-7786.MCR-24-0494

Yuhan Qiu, Andrew Chen, Rebecca Yu, Pablo Llevenes, Michael Seen, Naomi Y Ko, Stefano Monti, Gerald V Denis

{"title":"Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes.","authors":"Yuhan Qiu, Andrew Chen, Rebecca Yu, Pablo Llevenes, Michael Seen, Naomi Y Ko, Stefano Monti, Gerald V Denis","doi":"10.1158/1541-7786.MCR-24-0494","DOIUrl":"10.1158/1541-7786.MCR-24-0494","url":null,"abstract":"Patients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival. Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology and mechanisms that couple T2D to TNBC outcomes are poorly understood. Here we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72h). EMT, proliferation and angiogenesis were elevated in IR vs. control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR- 145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis. Implications: IR adipocyte exosomes modify the TME, enhance EMT, and promote brain metastasis-likely via miRNA pathways-suggesting that metabolic diseases like T2D foster a pro-metastatic TME, reducing survival, warranting close monitoring and potential metabolic interventions in TNBC patients with T2D.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566495","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

METTL3-Mediated m6A Modification Regulates the Polycomb Repressive Complex 1 Components BMI1 and RNF2 in Hepatocellular Carcinoma Cells. mettl3介导的m6A修饰调节肝癌细胞中多梳抑制复合体1 （PRC1）成分BMI1和RNF2。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0362

Weina Chen, Jinqiang Zhang, Wenbo Ma, Nianli Liu, Tong Wu

{"title":"METTL3-Mediated m6A Modification Regulates the Polycomb Repressive Complex 1 Components BMI1 and RNF2 in Hepatocellular Carcinoma Cells.","authors":"Weina Chen, Jinqiang Zhang, Wenbo Ma, Nianli Liu, Tong Wu","doi":"10.1158/1541-7786.MCR-24-0362","DOIUrl":"10.1158/1541-7786.MCR-24-0362","url":null,"abstract":"Methyltransferase-like 3 (METTL3) is a primary RNA methyltransferase that catalyzes N6-methyladenosine (m6A) modification. The current study aims to further delineate the effect and mechanism of METTL3 in hepatocellular carcinoma (HCC). By using a murine model of hepatocellular cancer development induced via hydrodynamic tail vein injection, we showed that METTL3 enhanced HCC development. In cultured human HCC cell lines (Huh7 and PLC/PRF/5), we observed that stable knockdown of METTL3 by short hairpin RNA significantly decreased tumor cell proliferation, colony formation, and invasion, in vitro. When Huh7 and PLC/PRF/5 cells with short hairpin RNA knockdown of METTL3 were inoculated into the livers of SCID mice, we found that METTL3 knockdown significantly inhibited the growth of HCC xenograft tumors. These findings establish METTL3 as an important oncogene in HCC. Through m6A sequencing, RNA sequencing, and subsequent validation studies, we identified BMI1 and RNF2, two key components of the polycomb repressive complex 1, as direct downstream targets of METTL3-mediated m6A modification in HCC cells. Our data indicated that METTL3 catalyzed m6A modification of BMI1 and RNF2 mRNAs which led to increased mRNA stability via the m6A reader proteins IGF2BP1/2/3. Furthermore, we showed that the METTL3 inhibitor, STM2457, significantly inhibited HCC cell growth in vitro and in mice. Collectively, this study provides novel evidence that METTL3 promotes HCC development and progression through m6A modification of BMI1 and RNF2. Our findings suggest that the METTL3-m6A-BMI1/RNF2 signaling axis may represent a new therapeutic target for the treatment of HCC. Implications: The METTL3-m6A-BMI1/RNF2 signaling axis promotes HCC development and progression.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"190-201"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770623","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