Molecular Cancer Research最新文献_第10页

Metabolic Hallmarks for Purine Nucleotide Biosynthesis in Small Cell Lung Carcinoma. 小细胞肺癌嘌呤核苷酸生物合成的代谢特征。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-01-02 DOI: 10.1158/1541-7786.MCR-23-0386

Sho Tabata, Shigeki Umemura, Miyu Narita, Hibiki Udagawa, Takamasa Ishikawa, Masahiro Tsuboi, Koichi Goto, Genichiro Ishii, Katsuya Tsuchihara, Atsushi Ochiai, Susumu S Kobayashi, Tomoyoshi Soga, Hideki Makinoshima

{"title":"Metabolic Hallmarks for Purine Nucleotide Biosynthesis in Small Cell Lung Carcinoma.","authors":"Sho Tabata, Shigeki Umemura, Miyu Narita, Hibiki Udagawa, Takamasa Ishikawa, Masahiro Tsuboi, Koichi Goto, Genichiro Ishii, Katsuya Tsuchihara, Atsushi Ochiai, Susumu S Kobayashi, Tomoyoshi Soga, Hideki Makinoshima","doi":"10.1158/1541-7786.MCR-23-0386","DOIUrl":"10.1158/1541-7786.MCR-23-0386","url":null,"abstract":"Small cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is involved in the malignant growth of SCLC, has emerged as a novel therapeutic target. Purine nucleotides are supplied by two pathways: de novo and salvage. However, the role of the salvage pathway in SCLC and the differences in utilization and crosstalk between the two pathways remain largely unclear. Here, we found that deletion of the HPRT1 gene, which codes for the rate-limiting enzyme of the purine salvage pathway, significantly suppressed tumor growth in vivo in several SCLC cells. We also demonstrated that HPRT1 expression confers resistance to lemetrexol (LMX), an inhibitor of the purine de novo pathway. Interestingly, HPRT1-knockout had less effect on SCLC SBC-5 cells, which are more sensitive to LMX than other SCLC cell lines, suggesting that a preference for either the purine de novo or salvage pathway occurs in SCLC. Furthermore, metabolome analysis of HPRT1-knockout cells revealed increased intermediates in the pentose phosphate pathway and elevated metabolic flux in the purine de novo pathway, indicating compensated metabolism between the de novo and salvage pathways in purine nucleotide biosynthesis. These results suggest that HPRT1 has therapeutic implications in SCLC and provide fundamental insights into the regulation of purine nucleotide biosynthesis.Implications: SCLC tumors preferentially utilize either the de novo or salvage pathway in purine nucleotide biosynthesis, and HPRT1 has therapeutic implications in SCLC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"82-93"},"PeriodicalIF":4.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10758693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41131834","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

Whole-Exome Sequencing Identifies Mutation Profile and Mutation Signature-Based Clustering Associated with Prognosis in Appendiceal Pseudomyxoma Peritonei. 全外显子组测序鉴定与腹膜假性粘液瘤预后相关的突变谱和基于突变特征的聚类。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-01-02 DOI: 10.1158/1541-7786.MCR-22-0801

Yu-Lin Lin, Jun-Qi Zhu, Rui-Qing Ma, Wei Meng, Zi-Yue Wang, Xin-Bao Li, Ru Ma, He-Liang Wu, Hong-Bin Xu, Ying Gao, Yan Li

{"title":"Whole-Exome Sequencing Identifies Mutation Profile and Mutation Signature-Based Clustering Associated with Prognosis in Appendiceal Pseudomyxoma Peritonei.","authors":"Yu-Lin Lin, Jun-Qi Zhu, Rui-Qing Ma, Wei Meng, Zi-Yue Wang, Xin-Bao Li, Ru Ma, He-Liang Wu, Hong-Bin Xu, Ying Gao, Yan Li","doi":"10.1158/1541-7786.MCR-22-0801","DOIUrl":"10.1158/1541-7786.MCR-22-0801","url":null,"abstract":"Pseudomyxoma peritonei (PMP) is a rare malignant clinical syndrome with little known about the global mutation profile. In this study, whole-exome sequencing (WES) was performed in 49 appendiceal PMP to investigate mutation profiles and mutation signatures. A total of 4,020 somatic mutations were detected, with a median mutation number of 56 (1-402). Tumor mutation burden (TMB) was generally low (median 1.55 mutations/Mb, 0.12-11.26 mutations/Mb). Mutations were mainly enriched in the function of cancer-related axonogenesis, extracellular matrix-related processes, calcium signaling pathway, and cAMP signaling pathway. Mutations in FCGBP, RBFOX1, SPEG, RTK-RAS, PI3K-AKT, and focal adhesion pathways were associated with high-grade mucinous carcinoma peritonei. These findings revealed distinct mutation profile in appendiceal PMP. Ten mutation signatures were identified, dividing patients into mutation signature cluster (MSC) 1 (N = 28, 57.1%) and MSC 2 (N = 21, 42.9%) groups. MSC (P = 0.007) was one of the four independent factors associated with 3-year survival. TMB (P = 0.003) and microsatellite instability (P = 0.002) were independent factors associated with MSC 2 grouping. Taken together, our findings provided a broader view in the understanding of molecular pathologic mechanism in appendiceal PMP and may be critical to developing an individualized approach to appendiceal PMP treatment.Implications: This work describes exhaustive mutation profile of PMP based on WES data and derives ten mutation signatures, which divides patients into two clusters and serve as an independent prognostic factor associated with 3-year survival.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"70-81"},"PeriodicalIF":4.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41179554","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

Distinct microRNA Signature and Suppression of ZFP36L1 Define ASCL1-Positive Lung Adenocarcinoma. 独特的微小RNA特征和ZFP36L1的抑制定义了ASCL1阳性肺腺癌。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-01-02 DOI: 10.1158/1541-7786.MCR-23-0229

Takayoshi Enokido, Masafumi Horie, Seiko Yoshino, Hiroshi I Suzuki, Rei Matsuki, Hans Brunnström, Patrick Micke, Takahide Nagase, Akira Saito, Naoya Miyashita

{"title":"Distinct microRNA Signature and Suppression of ZFP36L1 Define ASCL1-Positive Lung Adenocarcinoma.","authors":"Takayoshi Enokido, Masafumi Horie, Seiko Yoshino, Hiroshi I Suzuki, Rei Matsuki, Hans Brunnström, Patrick Micke, Takahide Nagase, Akira Saito, Naoya Miyashita","doi":"10.1158/1541-7786.MCR-23-0229","DOIUrl":"10.1158/1541-7786.MCR-23-0229","url":null,"abstract":"Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95-3p/miR-95-5p, miR-124-3p, and members of the miR-17∼92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124-3p and members of the miR-17∼92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124-3p, and IHC studies demonstrated that ASCL1-positive LUADs are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell-cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124-3p could modulate gene expression, providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive LUADs.Implications: Our study revealed unique miRNA profiles of ASCL1-positive LUADs and identified ASCL1-regulated miRNAs with functional relevance.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"29-40"},"PeriodicalIF":4.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41141928","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

The Role of the Gut Microbiome in Hematological Cancers. 肠道微生物组在血液系统癌症中的作用。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-01-02 DOI: 10.1158/1541-7786.MCR-23-0080

Najihah Hussein, Reena Rajasuriar, Asif M Khan, Yvonne Ai-Lian Lim, Gin Gin Gan

{"title":"The Role of the Gut Microbiome in Hematological Cancers.","authors":"Najihah Hussein, Reena Rajasuriar, Asif M Khan, Yvonne Ai-Lian Lim, Gin Gin Gan","doi":"10.1158/1541-7786.MCR-23-0080","DOIUrl":"10.1158/1541-7786.MCR-23-0080","url":null,"abstract":"Humans are in a complex symbiotic relationship with a wide range of microbial organisms, including bacteria, viruses, and fungi. The evolution and composition of the human microbiome can be an indicator of how it may affect human health and susceptibility to diseases. Microbiome alteration, termed as dysbiosis, has been linked to the pathogenesis and progression of hematological cancers. A variety of mechanisms, including epithelial barrier disruption, local chronic inflammation response trigger, antigen dis-sequestration, and molecular mimicry, have been proposed to be associated with gut microbiota. Dysbiosis may be induced or worsened by cancer therapies (such as chemotherapy and/or hematopoietic stem cell transplantation) or infection. The use of antibiotics during treatment may also promote dysbiosis, with possible long-term consequences. The aim of this review is to provide a succinct summary of the current knowledge describing the role of the microbiome in hematological cancers, as well as its influence on their therapies. Modulation of the gut microbiome, involving modifying the composition of the beneficial microorganisms in the management and treatment of hematological cancers is also discussed. Additionally discussed are the latest developments in modeling approaches and tools used for computational analyses, interpretation and better understanding of the gut microbiome data.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"7-20"},"PeriodicalIF":4.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71413230","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

Impact of Rare and Multiple Concurrent Gene Fusions on Diagnostic DNA Methylation Classifier in Brain Tumors. 罕见和多个并发基因融合对脑肿瘤诊断DNA甲基化分类器的影响。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-01-02 DOI: 10.1158/1541-7786.MCR-23-0627

Kristyn Galbraith, Jonathan Serrano, Guomiao Shen, Ivy Tran, Cheyanne C Slocum, Courtney Ketchum, Zied Abdullaev, Rust Turakulov, Tejus Bale, Marc Ladanyi, Purvil Sukhadia, Michael Zaidinski, Kerry Mullaney, Sara DiNapoli, Benjamin L Liechty, Marissa Barbaro, Jeffrey C Allen, Sharon L Gardner, Jeffrey Wisoff, David Harter, Eveline Teresa Hidalgo, John G Golfinos, Daniel A Orringer, Kenneth Aldape, Jamal Benhamida, Kazimierz O Wrzeszczynski, George Jour, Matija Snuderl

{"title":"Impact of Rare and Multiple Concurrent Gene Fusions on Diagnostic DNA Methylation Classifier in Brain Tumors.","authors":"Kristyn Galbraith, Jonathan Serrano, Guomiao Shen, Ivy Tran, Cheyanne C Slocum, Courtney Ketchum, Zied Abdullaev, Rust Turakulov, Tejus Bale, Marc Ladanyi, Purvil Sukhadia, Michael Zaidinski, Kerry Mullaney, Sara DiNapoli, Benjamin L Liechty, Marissa Barbaro, Jeffrey C Allen, Sharon L Gardner, Jeffrey Wisoff, David Harter, Eveline Teresa Hidalgo, John G Golfinos, Daniel A Orringer, Kenneth Aldape, Jamal Benhamida, Kazimierz O Wrzeszczynski, George Jour, Matija Snuderl","doi":"10.1158/1541-7786.MCR-23-0627","DOIUrl":"10.1158/1541-7786.MCR-23-0627","url":null,"abstract":"DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions.Implications: DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"21-28"},"PeriodicalIF":4.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10942665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691639","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

Identification of colorectal cancer cell stemness from single-cell RNA sequencing 通过单细胞 RNA 测序鉴定结直肠癌细胞干性

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2023-12-29 DOI: 10.1158/1541-7786.mcr-23-0468

Kangyu Lin, Saikat Chowdhury, Mohammad A. Zeineddine, Fadl A. Zeineddine, Nicholas J. Hornstein, Oscar E. Villarreal, Dipen M. Maru, Cara L. Haymaker, Jean-Nicolas Vauthey, George J. Chang, Elena Bogatenkova, David Menter, Scott Kopetz, John Paul Shen

{"title":"Identification of colorectal cancer cell stemness from single-cell RNA sequencing","authors":"Kangyu Lin, Saikat Chowdhury, Mohammad A. Zeineddine, Fadl A. Zeineddine, Nicholas J. Hornstein, Oscar E. Villarreal, Dipen M. Maru, Cara L. Haymaker, Jean-Nicolas Vauthey, George J. Chang, Elena Bogatenkova, David Menter, Scott Kopetz, John Paul Shen","doi":"10.1158/1541-7786.mcr-23-0468","DOIUrl":"https://doi.org/10.1158/1541-7786.mcr-23-0468","url":null,"abstract":"Cancer stem cells (CSCs) play a critical role in metastasis, relapse, and therapy resistance in colorectal cancer. While characterization of the normal lineage of cell development in the intestine has led to the identification of many genes involved in the induction and maintenance of pluripotency, recent studies suggest significant heterogeneity in CSC populations. Moreover, while many canonical colorectal cancer CSC marker genes have been identified, the ability to use these classical markers to annotate stemness at the single-cell level is limited. In this study, we performed single-cell RNA sequencing on a cohort of 6 primary colon, 9 liver metastatic tumors, and 11 normal (non-tumor) controls to identify colorectal CSCs at the single-cell level. Finding poor alignment of the 11 genes most used to identify colorectal CSC, we instead extracted a single-cell stemness signature (SCS_sig) that robustly identified ‘gold-standard’ colorectal CSCs that expressed all marker genes. Using this SCS_sig to quantify stemness, we found that while normal epithelial cells show a bimodal distribution, indicating distinct stem and differentiated states, in tumor epithelial cells stemness is a continuum, suggesting greater plasticity in these cells. The SCS_sig score was quite variable between different tumors, reflective of the known transcriptomic heterogeneity of CRC. Notably, patients with higher SCS_sig scores had significantly shorter disease-free survival time after curative intent surgical resection, suggesting stemness is associated with relapse. Implications: This study reveals significant heterogeneity of expression of genes commonly used to identify colorectal CSCs, and identifies a novel stemness signature to identify these cells from scRNAseq data.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139069783","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

Mitochondria transfer by platelet-derived microparticles regulates breast cancer bioenergetic states and malignant features 血小板衍生微颗粒的线粒体转移调节乳腺癌的生物能状态和恶性特征

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2023-12-12 DOI: 10.1158/1541-7786.mcr-23-0329

Vanessa Veilleux, Nicolas Pichaud, Luc H. Boudreau, Gilles A. Robichaud

{"title":"Mitochondria transfer by platelet-derived microparticles regulates breast cancer bioenergetic states and malignant features","authors":"Vanessa Veilleux, Nicolas Pichaud, Luc H. Boudreau, Gilles A. Robichaud","doi":"10.1158/1541-7786.mcr-23-0329","DOIUrl":"https://doi.org/10.1158/1541-7786.mcr-23-0329","url":null,"abstract":"An increasing number of studies show that platelets as well as platelet-derived microparticles (PMPs) play significant roles in cancer malignancy and disease progression. Particularly, PMPs have the capacity to interact and internalize within target cells resulting in the transfer of their bioactive cargo, which can modulate the signaling and activation processes of recipient cells. We recently identified a new subpopulation of these vesicles (termed mitoMPs), which contain functional mitochondria. Given the predominant role of mitochondria in cancer cell metabolism and disease progression, we set out to investigate the impact of mitoMPs on breast cancer metabolic reprograming and phenotypic processes leading to malignancy. Interestingly, we observed that recipient cell permeability to PMP internalization varied among the breast cancer cell types evaluated in our study. Specifically, cells permissive to mitoMPs acquire mitochondrial-dependent functions, which stimulate increased cellular oxygen consumption rates and intracellular ATP production. In addition, cancer cells co-incubated with PMPs display enhanced malignant features in terms of migration and invasion. Most importantly, the cancer aggressive processes and notable metabolic plasticity induced by PMPs were highly dependent on the functional status of the mitoMP-packaged mitochondria. These findings characterize a new mechanism by which breast cancer cells acquire foreign mitochondria resulting in the gain of metabolic processes and malignant features. A better understanding of these mechanisms may provide therapeutic opportunities through PMP blockade to deprive cancer cells from resources vital in disease progression. Implications: We show that the transfer of foreign mitochondria by microparticles modulates recipient cancer cell metabolic plasticity, leading to greater malignant processes.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"17 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138580253","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

Single-cell transcriptomics reveals pre-existing COVID-19 vulnerability factors in lung cancer patients 单细胞转录组学揭示肺癌患者原有的 COVID-19 易感因素

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2023-12-08 DOI: 10.1158/1541-7786.mcr-23-0692

Wendao Liu, Wenbo Li, Zhongming Zhao

{"title":"Single-cell transcriptomics reveals pre-existing COVID-19 vulnerability factors in lung cancer patients","authors":"Wendao Liu, Wenbo Li, Zhongming Zhao","doi":"10.1158/1541-7786.mcr-23-0692","DOIUrl":"https://doi.org/10.1158/1541-7786.mcr-23-0692","url":null,"abstract":"COVID-19 and cancer are major health threats, and individuals may develop both simultaneously. Recent studies have indicated that cancer patients are particularly vulnerable to COVID-19, but the molecular mechanisms underlying the associations remain poorly understood. To address this knowledge gap, we collected single-cell RNA sequencing data from COVID-19, lung adenocarcinoma, small cell lung carcinoma patients and normal lungs to perform an integrated analysis. We characterized altered cell populations, gene expression, and dysregulated intercellular communication in diseases. Our analysis identified pathological conditions shared by COVID-19 and lung cancer, including upregulated TMPRSS2 expression in epithelial cells, stronger inflammatory responses mediated by macrophages, increased T cell response suppression, and elevated fibrosis risk by pathological fibroblasts. These pre-existing conditions in lung cancer patients may lead to more severe inflammation, fibrosis, and weakened adaptive immune response upon COVID-19 infection. Our findings revealed potential molecular mechanisms driving an increased COVID-19 risk in lung cancer patients and suggested preventive and therapeutic targets for COVID-19 in this population. Implications: Our work reveals the potential molecular mechanisms contributing to the vulnerability to COVID-19 in lung cancer patients.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"12 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138560765","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

Generating a Murine PTEN Null Cell Line to Discover the Key Role of p110β-PAK1 in Castration-Resistant Prostate Cancer Invasion. 生成小鼠PTEN空细胞系发现p110β-PAK1在去势抵抗前列腺癌侵袭中的关键作用

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2023-12-01 DOI: 10.1158/1541-7786.MCR-22-0808

Haizhen Wang, Yu Zhou, Chen Chu, Jialing Xiao, Shanshan Zheng, Manav Korpal, Joshua M Korn, Tiffany Penaloza, Richard R Drake, Wenjian Gan, Xueliang Gao

{"title":"Generating a Murine PTEN Null Cell Line to Discover the Key Role of p110β-PAK1 in Castration-Resistant Prostate Cancer Invasion.","authors":"Haizhen Wang, Yu Zhou, Chen Chu, Jialing Xiao, Shanshan Zheng, Manav Korpal, Joshua M Korn, Tiffany Penaloza, Richard R Drake, Wenjian Gan, Xueliang Gao","doi":"10.1158/1541-7786.MCR-22-0808","DOIUrl":"10.1158/1541-7786.MCR-22-0808","url":null,"abstract":"Although androgen deprivation treatment often effectively decreases prostate cancer, incurable metastatic castration-resistant prostate cancer (CRPC) eventually occurs. It is important to understand how CRPC metastasis progresses, which is not clearly defined. The loss of PTEN, a phosphatase to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate in the PI3K pathway, occurs in up to 70% to 80% of CRPC. We generated a mouse androgen-independent prostate cancer cell line (PKO) from PTEN null and Hi-Myc transgenic mice in C57BL/6 background. We confirmed that this PKO cell line has an activated PI3K pathway and can metastasize into the femur and tibia of immunodeficient nude and immunocompetent C57BL/6 mice. In vitro, we found that androgen deprivation significantly enhanced PKO cell migration/invasion via the p110β isoform-depended PAK1-MAPK activation. Inhibition of the p110β-PAK1 axis significantly decreased prostate cancer cell migration/invasion. Of note, our analysis using clinical samples showed that PAK1 is more activated in CRPC than in advanced prostate cancer; high PAK1/phosphorylated-PAK1 levels are associated with decreased survival rates in patients with CRPC. All the information suggests that this cell line reflects the characteristics of CRPC cells and can be applied to dissect the mechanism of CRPC initiation and progression. This study also shows that PAK1 is a potential target for CRPC treatment.Implications: This study uses a newly generated PTEN null prostate cancer cell line to define a critical functional role of p110β-PAK1 in CRPC migration/invasion. This study also shows that the p110β-PAK1 axis can potentially be a therapeutic target in CRPC metastasis.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1317-1328"},"PeriodicalIF":5.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10030562","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

Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion. 白细胞介素-6通过Mitofusin 1介导的线粒体融合促进急性髓系白血病化疗耐药。

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2023-12-01 DOI: 10.1158/1541-7786.MCR-23-0382

Diyu Hou, Xiaoming Zheng, Danni Cai, Ruolan You, Jingru Liu, Xiaoting Wang, Xinai Liao, Maoqing Tan, Liyan Lin, Jin Wang, Shuxia Zhang, Huifang Huang

{"title":"Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion.","authors":"Diyu Hou, Xiaoming Zheng, Danni Cai, Ruolan You, Jingru Liu, Xiaoting Wang, Xinai Liao, Maoqing Tan, Liyan Lin, Jin Wang, Shuxia Zhang, Huifang Huang","doi":"10.1158/1541-7786.MCR-23-0382","DOIUrl":"10.1158/1541-7786.MCR-23-0382","url":null,"abstract":"Acute myeloid leukemia (AML), an aggressive hematopoietic malignancy, exhibits poor prognosis and a high recurrence rate largely because of primary and secondary drug resistance. Elevated serum IL6 levels have been observed in patients with AML and are associated with chemoresistance. Chemoresistant AML cells are highly dependent on oxidative phosphorylation (OXPHOS), and mitochondrial network remodeling is essential for mitochondrial function. However, IL6-mediated regulation of mitochondrial remodeling and its effectiveness as a therapeutic target remain unclear. We aimed to determine the mechanisms through which IL6 facilitates the development of chemoresistance in AML cells. IL6 upregulated mitofusin 1 (MFN1)-mediated mitochondrial fusion, promoted OXPHOS, and induced chemoresistance in AML cells. MFN1 knockdown impaired the effects of IL6 on mitochondrial function and chemoresistance in AML cells. In an MLL::AF9 fusion gene-induced AML mouse model, IL6 reduced chemosensitivity to cytarabine (Ara-C), a commonly used antileukemia drug, accompanied by increased MFN1 expression, mitochondrial fusion, and OXPHOS status. In contrast, anti-IL6 antibodies downregulated MFN1 expression, suppressed mitochondrial fusion and OXPHOS, enhanced the curative effects of Ara-C, and prolonged overall survival. In conclusion, IL6 upregulated MFN1-mediated mitochondrial fusion in AML, which facilitated mitochondrial respiration, in turn, inducing chemoresistance. Thus, targeting IL6 may have therapeutic implications in overcoming IL6-mediated chemoresistance in AML.Implications: IL6 treatment induces MFN1-mediated mitochondrial fusion, promotes OXPHOS, and confers chemoresistance in AML cells. Targeting IL6 regulation in mitochondria is a promising therapeutic strategy to enhance the chemosensitivity of AML.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1366-1378"},"PeriodicalIF":5.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10216638","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}

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