Cancer Communications最新文献

{"title":"Enhancing sensitivity of triple-negative breast cancer to DNA-damaging therapy through chemical inhibition of the m6A methyltransferase METTL3","authors":"Bianca Cesaro,&nbsp;Alessia Iaiza,&nbsp;Fabio Piscopo,&nbsp;Marco Tarullo,&nbsp;Eleonora Cesari,&nbsp;Dante Rotili,&nbsp;Antonello Mai,&nbsp;Alberto Diana,&nbsp;Michela Londero,&nbsp;Luca Del Giacco,&nbsp;Riccardo Masetti,&nbsp;Alba Di Leone,&nbsp;Chiara Naro,&nbsp;Silvia Masciarelli,&nbsp;Giulia Fontemaggi,&nbsp;Claudio Sette,&nbsp;Francesco Fazi,&nbsp;Alessandro Fatica","doi":"10.1002/cac2.12509","DOIUrl":"10.1002/cac2.12509","url":null,"abstract":"<p>Dear Editor,</p><p>N⁶-methyladenosine (m⁶A) is a critical mRNA modification catalyzed by the enzyme methyltransferase-like 3 (METTL3), with implications in RNA metabolism. METTL3 upregulation is associated with cancer progression, metastasis, and drug resistance, making it a potential therapeutic target [<span>1</span>]. The small-molecule METTL3 inhibitor, STM2457, has shown promise in treating acute myeloid leukemia (AML) and has demonstrated good tolerance in mice [<span>2, 3</span>]. However, the specific cancer types where METTL3 inhibitors are most effective remain unknown.</p><p>In breast cancer, <i>METTL3</i> knockdown markedly suppresses proliferation, invasiveness, and metastasis [<span>4</span>]. Therefore, METTL3 inhibition is proposed as a therapeutic approach for breast cancer. Triple-negative breast cancer (TNBC), the most aggressive subtype, lacks targeted therapies, and its primary treatments involve conventional chemotherapy and DNA-damaging agents [<span>5</span>]. Homologous recombination deficiency, such as mutations in the breast cancer gene 1 (<i>BRCA1</i>) and <i>BRCA2</i>, serves as a predictive biomarker for identifying patients who would benefit from genotoxic chemotherapy and poly(ADP-ribose) polymerase (<i>PARP</i>) inhibitors. Notably, METTL3 is recruited to DNA-damaged sites and is crucial for subsequent DNA repair [<span>6, 7</span>]. Consequently, <i>METTL3</i> knockdown reduces DNA repair activity and sensitizes cancer cells to genotoxic drugs [<span>7, 8</span>]. However, while TNBC exhibits elevated METTL3 levels, and its nuclear catalytic activity associates with invasiveness and metastasis [<span>9</span>], it remains uncertain whether METTL3 inhibition enhances chemotherapy response in TNBC.</p><p>Here, we aimed to explore the potential of METTL3 catalytic inhibition by STM2457 as a valuable treatment option for TNBC. Furthermore, we assessed the impact of STM2457 on the sensitivity of TNBC cells and a TNBC patient-derived organoid line to clinical DNA-damaging therapies, like platinum-based chemotherapy and the PARP inhibitor olaparib (Supplementary file of methods).</p><p>STM2457 significantly reduced the proliferation and viability of TNBC cells, including both <i>BRCA1/2</i> wild-type (MDA-MB-231 and MDA-MB-468) and <i>BRCA1</i>-mutated (MDA-MB-436, HCC1395, and HCC1937) cell lines. STM2457 exhibited negligible effects on the proliferation of non-tumoral breast epithelial cells (MCF-10A), with significant reduction observed only at the highest concentration tested (100 μmol/L) (Figure 1A, Supplementary Figure S1A-B). The treatment with 10 μmol/L STM2457 for 48 h decreased the global m⁶A levels in mRNA by approximately 50% in both MDA-MB-231 and MCF-10A cells (Supplementary Figure S1C). Colony formation assays further confirmed the anti-proliferative impact of STM2457 on TNBC cell lines (Figure 1B, Supplementary Figure S2). Moreover, wound healing assays indicated that ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138741751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 43, Issue 12","authors":"Yuting Li,&nbsp;Hanhao Zheng,&nbsp;Yuming Luo,&nbsp;Yan Lin,&nbsp;Mingjie An,&nbsp;Yao Kong,&nbsp;Yue Zhao,&nbsp;Yina Yin,&nbsp;Le Ai,&nbsp;Jian Huang,&nbsp;Changhao Chen","doi":"10.1002/cac2.12508","DOIUrl":"https://doi.org/10.1002/cac2.12508","url":null,"abstract":"<p>The cover image is based on the Original Article <i>An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis</i> by Yuting Li et al., https://doi.org/10.1002/cac2.12470.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138475622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA-CCAT5-mediated crosstalk between Wnt/β-Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity","authors":"Chenchen Liu,&nbsp;Aiwen Shen,&nbsp;Junquan Song,&nbsp;Lei Cheng,&nbsp;Meng Zhang,&nbsp;Yanong Wang,&nbsp;Xiaowen Liu","doi":"10.1002/cac2.12507","DOIUrl":"10.1002/cac2.12507","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Although the constitutively activated Wnt/β-catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non-coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt-transactivated lncRNA, colon cancer-associated transcript 5 (CCAT5), in GC metastasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>LncRNA-sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation-resistant β-catenin (S33Y mutated) in ascites-derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)-re-ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA-sequencing, mass spectrometry, and CRISPR/Cas9-knocknout system. The therapeutic potential of CCAT5 was examined through RNAi-based cell xenograft model and patient-derived xenograft (PDX) model of IPD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified a novel Wnt-regulated lncRNA, CCAT5, which was transactivated by the β-catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C-end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1)-mediated STAT3^Y705 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β-catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt-drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si-CCAT5 selectively attenuated growth and metastasis of Wnt^high GC, but not Wnt^low GC. The combination of si-CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnt^high PDX mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified a novel Wnt-transactivated lncRNA, CCAT5. Our study r","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12507","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138443897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell and bulk transcriptomics identifies a tumor-specific CD36⁺ cancer-associated fibroblast subpopulation in colorectal cancer.","authors":"Jin Wang, Ming-Jia Xi, Qing Lu, Bi-Han Xia, Yu-Zhi Liu, Jin-Lin Yang","doi":"10.1002/cac2.12506","DOIUrl":"https://doi.org/10.1002/cac2.12506","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138290446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omic study to unmask genes involved in prostate cancer development in a multi-case family","authors":"Lucia Chica-Redecillas,&nbsp;Sergio Cuenca-Lopez,&nbsp;Eduardo Andres-Leon,&nbsp;Laura Carmen Terron-Camero,&nbsp;Blanca Cano-Gutierrez,&nbsp;Jose Manuel Cozar,&nbsp;Jose Antonio Lorente,&nbsp;Fernando Vazquez-Alonso,&nbsp;Luis Javier Martinez-Gonzalez,&nbsp;Maria Jesus Alvarez-Cubero","doi":"10.1002/cac2.12501","DOIUrl":"10.1002/cac2.12501","url":null,"abstract":"<p>Dear Editor,</p><p>Hereditary prostate cancer (PC) comprises 5%-10% of all PC cases. The increased risk of PC in men with a family history of the disease is well known and is commonly caused by germline mutations, leading to clinical guidelines mentioning various genes for identifying high-risk individuals. However, the complex inheritance patterns involving multiple single nucleotide polymorphisms (SNPs) make it a genetically heterogeneous disease, with genetic testing still in its early stages. Current guidelines, such as those from the National Comprehensive Cancer Network (NCCN), are insufficient to identify and stratify all PC patients [<span>1</span>]. To improve testing and screening for familial PC, we report a multi-omic analysis (Supplementary Figures S1-S2) in a PC multi-case family of seven members (two healthy, four PC, and one breast cancer) (Figure 1A, Supplementary Table S1) combining exome, transcriptome and epigenomic analyses (whole-DNA methylation and small-RNA sequencing), offering a unique perspective on the understanding of hereditary PC to date. Each family is a small genetic unit that differs significantly from others with the same pathology but different genetic origins. Therefore, individualized studies may be the key to unravel the heterogeneity of this disease. However, we need to consider that conducting futuremetabolomic analysis would be next steps to reinforce present data, as well as reproducible analysis in other PC families.</p><p>We selected 34 genes based on NCCN (v1.2023) and European Association of Urology (EAU, v2.0) clinical guidelines and literature [<span>2, 3</span>] (Supplementary Table S2). We found 268 variants in 26 of these genes (<i>APC, ATM, AXIN2, BARD1, BMPR1A, BRCA1/2, CDH1, CDK4, CHEK2, DICER1, MLH1, MSH2/3/6, MUTYH, NF1, PMS2, POLD1, POLE, PTEN, RAD51C/D, SMAD4, STK11</i> and <i>TP53</i>), most of which were intronic (91.4%) and/or unreported (84.3%) (Supplementary Figure S3 and Supplementary Table S3). In addition, genome-wide analysis of high-impact variants revealed only four mutations affecting the major isoforms of the <i>ANAPC1</i>, <i>HIBCH</i>, and <i>MOK</i>, but none of these genes have been previously reported in PC (Supplementary Table S4). Interestingly, despite being high-risk cancer patients, the individuals in the present study's family did not show any pathogenic mutations in the genes specified by clinical guidelines. Furthermore, this is added to the growing evidence for the potential of non-coding mutations, both near-exonic and deep-intronic mutations, in carcinogenesis. There is already evidence of how known tumor suppressor genes are affected by intronic mutations [<span>4</span>]. Exome analysis also reported ten identical mutations in three genes, one in <i>AXIN2</i>, two in <i>DICER1</i> and seven in <i>BARD1</i>, in all PC patients (Supplementary Table S3), suggesting that these mutations may be responsible for the development of cancer in this family. Among th","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138290445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Management of locally advanced non-small cell lung cancer: State of the art and future directions","authors":"Da Miao,&nbsp;Jing Zhao,&nbsp;Ying Han,&nbsp;Jiaqi Zhou,&nbsp;Xiuzhen Li,&nbsp;Ting Zhang,&nbsp;Wen Li,&nbsp;Yang Xia","doi":"10.1002/cac2.12505","DOIUrl":"10.1002/cac2.12505","url":null,"abstract":"<p>Lung cancer is the second most common and the deadliest type of cancer worldwide. Clinically, non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer; approximately one-third of affected patients have locally advanced NSCLC (LA-NSCLC, stage III NSCLC) at diagnosis. Because of its heterogeneity, LA-NSCLC often requires multidisciplinary assessment. Moreover, the prognosis of affected patients is much below satisfaction, and the efficacy of traditional therapeutic strategies has reached a plateau. With the emergence of targeted therapies and immunotherapies, as well as the continuous development of novel radiotherapies, we have entered an era of novel treatment paradigm for LA-NSCLC. Here, we reviewed the landscape of relevant therapeutic modalities, including adjuvant, neoadjuvant, and perioperative targeted and immune strategies in patients with resectable LA-NSCLC with/without oncogenic alterations; as well as novel combinations of chemoradiation and immunotherapy/targeted therapy in unresectable LA-NSCLC. We addressed the unresolved challenges that remain in the field, and examined future directions to optimize clinical management and increase the cure rate of LA-NSCLC.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12505","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138175681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 43, Issue 11","authors":"Ai Zhuang,&nbsp;Xiang Gu,&nbsp;Tongxin Ge,&nbsp;Shaoyun Wang,&nbsp;Shengfang Ge,&nbsp;Peiwei Chai,&nbsp;Renbing Jia,&nbsp;Xianqun Fan","doi":"10.1002/cac2.12504","DOIUrl":"https://doi.org/10.1002/cac2.12504","url":null,"abstract":"<p>The cover image is based on the Original Article <i>Targeting histone deacetylase suppresses tumor growth through eliciting METTL14-modified m⁶A RNA methylation in ocular melanoma</i> by Ai Zhuang et al., https://doi.org/10.1002/cac2.12471.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137811202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 43, Issue 11","authors":"Yongzhan Nie,&nbsp;Xianchun Gao,&nbsp;Xiqiang Cai,&nbsp;Zhen Wu,&nbsp;Qiaoyi Liang,&nbsp;Guobing Xu,&nbsp;Na Liu,&nbsp;Peng Gao,&nbsp;Jingyu Deng,&nbsp;Hongzhi Xu,&nbsp;Zhanlong Shen,&nbsp;Changqi Cao,&nbsp;Fenrong Chen,&nbsp;Nannan Zhang,&nbsp;Yongxi Song,&nbsp;Mingjun Sun,&nbsp;Chengyin Liu,&nbsp;Guangpeng Zhou,&nbsp;Weili Han,&nbsp;Jianhua Dou,&nbsp;Huahong Xie,&nbsp;Liping Yao,&nbsp;Zhiguo Liu,&nbsp;Gang Ji,&nbsp;Xin Wang,&nbsp;Qingchuan Zhao,&nbsp;Lei Shang,&nbsp;Daiming Fan,&nbsp;Xiaoliang Han,&nbsp;Jianlin Ren,&nbsp;Han Liang,&nbsp;Zhenning Wang,&nbsp;Jinhai Wang,&nbsp;Qi Wu,&nbsp;Jun Yu,&nbsp;Kaichun Wu,&nbsp;the MAGIS Study Group","doi":"10.1002/cac2.12503","DOIUrl":"https://doi.org/10.1002/cac2.12503","url":null,"abstract":"<p>The cover image is based on the Correspondence <i>Combining methylated SEPTIN9 and RNF180 plasma markers for diagnosis and early detection of gastric cancer</i> by Yongzhan Nie et al., https://doi.org/10.1002/cac2.12478.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12503","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137811201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-targeted atovaquone promotes anti-lung cancer immunity by reshaping tumor microenvironment and enhancing energy metabolism of anti-tumor immune cells","authors":"Donghai Xiong,&nbsp;Zheng Yin,&nbsp;Mofei Huang,&nbsp;Yian Wang,&nbsp;Micael Hardy,&nbsp;Balaraman Kalyanaraman,&nbsp;Stephen T Wong,&nbsp;Ming You","doi":"10.1002/cac2.12500","DOIUrl":"10.1002/cac2.12500","url":null,"abstract":"<p>Atovaquone (ATO), a mitochondrial inhibitor, has anti-cancer effects [<span>1</span>]. Based on ATO, we developed mitochondria-targeted atovaquone (Mito-ATO) that had even stronger anti-tumor efficacy than ATO [<span>2</span>]. We synthesized Mito-ATO by attaching the bulky triphenylphosphonium (TPP) group to ATO via a ten-carbon alkyl chain (Supplementary file of methods; Supplementary Figure S1). To assess the effects of Mito-ATO on tumor microenvironment, we conducted single-cell RNA-sequencing (scRNA-seq) on treated immune cells from mice having lung tumors either treated with or without Mito-ATO. Seurat was used for clustering and annotation of CD45⁺ immune cells [<span>3</span>]. The detected lymphoid cell populations were CD8⁺ T cells, CD4⁺ T cells, regulatory T cells (Tregs), gamma-delta T (Tgd) cells, B cells, and natural killer (NK) cells; and the myeloid cells identified were macrophages, neutrophils, plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs) and mast cells (Figure 1A-C). Clustering of CD4⁺ T cells into seven subpopulations, the separation of neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs), and the division of macrophages into M1 and M2 subtypes were described in our previous publication [<span>2</span>]. In this study, we further divided CD8⁺ T cells into four subpopulations, i.e., exhausted CD8⁺ T (CD8T_Exhausted) cells, memory like CD8⁺ T (CD8T_MemoryLike) cells, effector memory like CD8⁺ T (CD8T_EffectorMemory) cells and naive CD8⁺ T (CD8T_Naive) cells, using the tumor-infiltrating CD8⁺ lymphocyte state predictor (TILPRED) method [<span>4</span>] (Figure 1D-E). Probability scores computed with TILPRED could discriminate CD8T_Exhausted from CD8T_MemoryLike cells despite overlap between the two subsets on UMAP representation (Supplementary Figure S2). Mito-ATO treatment significantly decreased the proportion of the CD8T_Exhausted cells (7.3% vs. 32.5%, <i>P</i> &lt; 0.001) but increased the proportion of anti-tumor CD8T_EffectorMemory cells as compared with vehicle treatment (37.3% vs. 11.9%, <i>P</i> &lt; 0.001) (Figure 1F). In comparison, the percentages of CD8⁺ T cells out of total T cells were not different between the two groups (Supplementary Table S1). For validation, we verified that Mito-ATO treatment induced changes in CD8⁺ T cell repartition by conducting flow cytometry. Mito-ATO treatment significantly increased the percentage of cytotoxic tumor necrosis factor-alpha (TNF-α)⁺CD8⁺ T cells and decreased the percentage of programmed cell death protein-1 (PD-1)⁺ T cell immunoglobulin and mucin domain-containing protein 3 (TIM3)⁺CD8⁺ T cells (Supplementary Figure S3). These matched the scRNA-seq results. We also observed a slight trend toward the upregulation of genes involved in CD8<su","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12500","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71478363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma","authors":"Xiaoteng Cui,&nbsp;Jixing Zhao,&nbsp;Guanzhang Li,&nbsp;Chao Yang,&nbsp;Shixue Yang,&nbsp;Qi Zhan,&nbsp;Junhu Zhou,&nbsp;Yunfei Wang,&nbsp;Menglin Xiao,&nbsp;Biao Hong,&nbsp;Kaikai Yi,&nbsp;Fei Tong,&nbsp;Yanli Tan,&nbsp;Hu Wang,&nbsp;Qixue Wang,&nbsp;Tao Jiang,&nbsp;Chuan Fang,&nbsp;Chunsheng Kang","doi":"10.1002/cac2.12502","DOIUrl":"10.1002/cac2.12502","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms. Epidermal growth factor receptor (<i>EGFR</i>) amplification and <i>EGFR-vIII</i> mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis. A metabolism-associated RTK-fatty acid-gene signature was constructed and verified. MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3 (ACSS3), acyl-CoA synthetase long-chain family member 3 (ACSL3), and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF-κB-dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71420969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}