Cancer Communications最新文献

{"title":"Revealing the secret behind Epstein-Barr virus-specific tumor immune contexture","authors":"Chu-Xia Deng","doi":"10.1002/cac2.12529","DOIUrl":"10.1002/cac2.12529","url":null,"abstract":"<p>Immune checkpoint inhibitor (ICI) therapy has significantly revolutionized cancer treatment across various malignancies, offering distinct and enduring clinical advantages [<span>1</span>]. Gastric cancer (GC) represents a widespread and life-threatening malignancy with substantial global health implications [<span>2</span>]. However, ICI therapy has not produced satisfactory therapeutic responses in GC patients. Presently, monotherapy targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway demonstrates clinical efficacy in approximately 10% of GC patients [<span>3</span>]. Exploration of novel immunotherapeutic targets is urgently needed. Notably, Epstein-Barr virus (EBV)-positive GC constitutes a distinct GC subset, exhibiting a remarkably higher objective response rate to anti-PD-1 inhibitors—an intriguing phenomenon [<span>4</span>]. Several studies have found that EBV-positive GC has more innate and adaptive immune cell infiltration than EBV-negative GC [<span>5, 6</span>]. In their recent publication titled “Dynamic single-cell mapping reveals Epstein-Barr virus-imprinted T-cell exhaustion and on-treatment response”, Qiu <i>et al.</i> [<span>7</span>] unveiled, for the first time, the cellular basis underlying these remarkably heightened responses in EBV-positive GC patients undergoing immunochemotherapy. Leveraging single-cell profiling technologies, this study deepened our comprehension of the intricate and heterogeneous tumor microenvironment in GC.</p><p>In this study, the authors conducted a comprehensive characterization of the cellular dynamics of tumor-infiltrating immune cells in GC patients, distinguishing between those with EBV-positive and EBV-negative statuses. EBV-positive GC exhibited a heightened immune phenotype characterized by elevated infiltration of T cells and B cells, highlighting the intricate interplay among EBV infection, multi-cellular ecosystems, and tumor development. EBV-negative GC exhibited an immune-suppressive tumor microenvironment characterized by an abundance of plasma cells, myeloid cells, and mast cells. After treatment, the evaluation of the dynamic changes in EBV-positive GC showed an increased presence of cytotoxic CD8<sup>+</sup> T cells and effector memory/memory CD8<sup>+</sup> T cells. Notably, there was clear evidence of clonal revival and reinvigoration of CD8<sup>+</sup> T cells in EBV-positive GC patients, indicating an active T cell-mediated immune reaction enhancing treatment responses.</p><p>Furthermore, the authors observed a distinct EBV-imprinted CD8<sup>+</sup> T cell population, ISG-15<sup>+</sup>CD8<sup>+</sup> T cells, which exhibited significantly higher expression of interferon-stimulated genes, such as ISG-15, IFIT1-3, RASD2, and MX1. Significantly, ISG-15<sup>+</sup>CD8<sup>+</sup> T cells demonstrated the ability to recognize EBV antigens and coordinated exhausted T cell responses. STARTRAC-tran analysis revealed a robust association bet","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"491-494"},"PeriodicalIF":16.2,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12529","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038740","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":"Unveiling quality of clinical trial in China: from concern to confirmation","authors":"Huiyao Huang, Yiru Hou, Hong Fang, Ling Xu, Yue Yu, Huifang Zhang, Jing Zhang, Yu Tang, Gongtao Lan, Wenbao Zhang, Ning Li","doi":"10.1002/cac2.12528","DOIUrl":"10.1002/cac2.12528","url":null,"abstract":"<p>The cornerstone of scientifically valid and ethically sound clinical trials is in compliance with established global quality requirements. Although China has made significant progress over the past 20 years in terms of the clinical trial quantity [<span>1</span>], quality and participation in multiregional trials [<span>2</span>], there still remain concerns regarding the trial quality, which could be associated with the self-inspection initiative in 2015 [<span>3</span>].</p><p>In fact, the clinical trial quality in China has improved significantly during the past decade, which is reflected in the harmonized development trends of industry quality systems and regulatory quality promotion systems (Figure 1). In 2003, the China Good Clinical Practice (GCP) guidelines have been released, which identified the subject protection and data integrity as two basic principles of clinical trials. Four rigorous management policies started to implement in 2015, which required sponsors to re-evaluate the authenticity, integrity, and compliance of trial data before new drug application [<span>4</span>]. A series of high-profile policies were subsequently announced by the National Medical Products Administration, to improve quality ecosystem [<span>5</span>]. The regulatory supervision of trial quality in China has been significantly strengthened since then. In the meantime, a vital shift occurred since the quality culture in the industry emerged, and the approaches and tools of quality management systems were launched through information exchange and training.</p><p>Another milestone of trial quality progress in China was that China officially joined the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and began to integrate into the international drug regulatory system. This alliance initiated a proactive and harmonized process with China pledging to gradually transform its pharmaceutical regulatory authorities, industry and institutions to implement the international coalition's technical standards and guidelines [<span>6</span>]. Universal quality standard GCP guidelines and ideas, such as quality by design (QbD) and risk-based inspection, could be implemented almost simultaneously in China. Gradually, trial quality culture has been embedded in the full life cycle of drug research and development (R&D) in China.</p><p>All four regions, including China, the European Union (EU), the United States (US) and Japan, have a common consensus and harmonized standards to ensure the participants’ safety, data integrity and GCP compliance, and all have established similar regulatory frameworks for quality compliance (Supplementary Table S1). For example, local and international GCP standards and principles should be established, then inspection processes and checklists with key points for investigational drugs should be employed. In terms of inspection objects, types, requirements and disclosure, we observed cons","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 5","pages":"576-579"},"PeriodicalIF":16.2,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12528","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038741","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":"Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study","authors":"Jing Zheng,&nbsp;Tao Wang,&nbsp;Yunpeng Yang,&nbsp;Jie Huang,&nbsp;Jifeng Feng,&nbsp;Wu Zhuang,&nbsp;Jianhua Chen,&nbsp;Jun Zhao,&nbsp;Wei Zhong,&nbsp;Yanqiu Zhao,&nbsp;Yiping Zhang,&nbsp;Yong Song,&nbsp;Yi Hu,&nbsp;Zhuang Yu,&nbsp;Youling Gong,&nbsp;Yuan Chen,&nbsp;Feng Ye,&nbsp;Shucai Zhang,&nbsp;Lejie Cao,&nbsp;Yun Fan,&nbsp;Gang Wu,&nbsp;Yubiao Guo,&nbsp;Chengzhi Zhou,&nbsp;Kewei Ma,&nbsp;Jian Fang,&nbsp;Weineng Feng,&nbsp;Yunpeng Liu,&nbsp;Zhendong Zheng,&nbsp;Gaofeng Li,&nbsp;Huijie Wang,&nbsp;Shundong Cang,&nbsp;Ning Wu,&nbsp;Wei Song,&nbsp;Xiaoqing Liu,&nbsp;Shijun Zhao,&nbsp;Lieming Ding,&nbsp;Giovanni Selvaggi,&nbsp;Yang Wang,&nbsp;Shanshan Xiao,&nbsp;Qian Wang,&nbsp;Zhilin Shen,&nbsp;Jianya Zhou,&nbsp;Jianying Zhou,&nbsp;Li Zhang","doi":"10.1002/cac2.12524","DOIUrl":"10.1002/cac2.12524","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (<i>ALK</i>)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline <i>ALK</i> or tumor protein 53 (<i>TP53</i>) mutation. In addition, patients with concurrent <i>TP53</i> mutations had shorter OS than those without concurrent <i>TP53</i> mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated <i>ALK</i> mutation abundance at 6 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and <i>ALK</i>-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"455-468"},"PeriodicalIF":16.2,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12524","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995723","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":"Targeting autophagy overcomes cancer-intrinsic resistance to CAR-T immunotherapy in B-cell malignancies","authors":"Lu Tang,&nbsp;Huan Zhang,&nbsp;Fen Zhou,&nbsp;Qiuzhe Wei,&nbsp;Mengyi Du,&nbsp;Jianghua Wu,&nbsp;Chenggong Li,&nbsp;Wenjing Luo,&nbsp;Jie Zhou,&nbsp;Xindi Wang,&nbsp;Zhaozhao Chen,&nbsp;Yinqiang Zhang,&nbsp;Zhongpei Huang,&nbsp;Zhuolin Wu,&nbsp;Yuxi Wen,&nbsp;Huiwen Jiang,&nbsp;Danying Liao,&nbsp;Haiming Kou,&nbsp;Wei Xiong,&nbsp;Heng Mei,&nbsp;Yu Hu","doi":"10.1002/cac2.12525","DOIUrl":"10.1002/cac2.12525","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Chimeric antigen receptor T (CAR-T) therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignancies, but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood. This study aims to explore the molecular determinants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing. The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells. In addition, the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The CRISPR/Cas9-based knockout screening showed that the enrichment of autophagy-related genes (&lt;i&gt;ATG3&lt;/i&gt;, &lt;i&gt;BECN1&lt;/i&gt;, and &lt;i&gt;RB1CC1&lt;/i&gt;) provided protection of cancer cells from CD19 CAR-T cell-mediated cytotoxicity. These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy. Notably, higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer responsiveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy. Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell therapy. Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma. Moreover, our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings confirm that autophagy signaling in B-cell malignancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell i","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 3","pages":"408-432"},"PeriodicalIF":16.2,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12525","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970976","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":"SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation","authors":"Shiyu Zhang,&nbsp;Xing Jia,&nbsp;Haojiang Dai,&nbsp;Xingxin Zhu,&nbsp;Wenfeng Song,&nbsp;Suchen Bian,&nbsp;Hao Wu,&nbsp;Shinuo Chen,&nbsp;Yangbo Tang,&nbsp;Junran Chen,&nbsp;Cheng Jin,&nbsp;Mengqiao Zhou,&nbsp;Haiyang Xie,&nbsp;Shusen Zheng,&nbsp;Penghong Song","doi":"10.1002/cac2.12527","DOIUrl":"10.1002/cac2.12527","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Liver cancer is a malignancy with high morbidity and mortality rates. Serpin family E member 2 (SERPINE2) has been reported to play a key role in the metastasis of many tumors. In this study, we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The Cancer Genome Atlas database (TCGA), including DNA methylation and transcriptome sequencing data, was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver cancer. Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clinical parameters of patients. DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells. RNA sequencing, cytokine assays, immunoprecipitation (IP) and mass spectrometry (MS) assays, protein stability assays, and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis. Patient-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Based on the public database screening, SERPINE2 was identified as a tumor promoter regulated by DNA methylation. SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer. SERPINE2 promoted liver cancer metastasis by enhancing cell pseudopodia formation, cell adhesion, cancer-associated fibroblast activation, extracellular matrix remodeling, and angiogenesis. IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor (EGFR) and its downstream signaling pathways by interacting with EGFR. Mechanistically, SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase, c-Cbl. Additionally, EGFR was activated in liver cancer cells after sorafenib treatment, and SERPINE2 knockdown-induced EGFR downregulation significantly enhanced the therapeutic efficacy of sorafenib against liver cancer. Furthermore, we found that SERPINE2 knockdown also had a sensitizing effect on lenvatinib treatment.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;SERPINE2 promoted liver cancer metastasis by preventing EGFR degradation via c-Cbl-mediated ubiquitination, suggesting that inhibition of the SERPINE2-EGFR axis may be a potenti","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 3","pages":"384-407"},"PeriodicalIF":16.2,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12527","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970975","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":"NAT10-mediated ac4C-modified ANKZF1 promotes tumor progression and lymphangiogenesis in clear-cell renal cell carcinoma by attenuating YWHAE-driven cytoplasmic retention of YAP1","authors":"Daojia Miao,&nbsp;Jian Shi,&nbsp;Qingyang Lv,&nbsp;Diaoyi Tan,&nbsp;Chuanyi Zhao,&nbsp;Zhiyong Xiong,&nbsp;Xiaoping Zhang","doi":"10.1002/cac2.12523","DOIUrl":"10.1002/cac2.12523","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lymphatic metastasis is one of the most common metastatic routes and indicates a poor prognosis in clear-cell renal cell carcinoma (ccRCC). N-acetyltransferase 10 (NAT10) is known to catalyze N4-acetylcytidine (ac⁴C) modification of mRNA and participate in many cellular processes. However, its role in the lymphangiogenic process of ccRCC has not been reported. This study aimed to elucidate the role of NAT10 in ccRCC lymphangiogenesis, providing valuable insights into potential therapeutic targets for intervention.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>ac⁴C modification and NAT10 expression levels in ccRCC were assessed using public databases and clinical samples. Functional investigations involved manipulating NAT10 expression in cellular and mouse models to study its role in ccRCC. Mechanistic insights were gained through a combination of RNA sequencing, mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, and site-specific mutation analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that ac⁴C modification and NAT10 expression levels increased in ccRCC. NAT10 promoted tumor progression and lymphangiogenesis of ccRCC by enhancing the nuclear import of Yes1-associated transcriptional regulator (YAP1). Subsequently, we identified ankyrin repeat and zinc finger peptidyl tRNA hydrolase 1 (ANKZF1) as the functional target of NAT10, and its upregulation in ccRCC was caused by NAT10-mediated ac⁴C modification. Mechanistic analyses demonstrated that ANKZF1 interacted with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE) to competitively inhibit cytoplasmic retention of YAP1, leading to transcriptional activation of pro-lymphangiogenic factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These results suggested a pro-cancer role of NAT10-mediated acetylation in ccRCC and identified the NAT10/ANKZF1/YAP1 axis as an under-reported pathway involving tumor progression and lymphangiogenesis in ccRCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 3","pages":"361-383"},"PeriodicalIF":16.2,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12523","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970974","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":"A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy","authors":"Yingqiang Liu,&nbsp;Linjiang Tong,&nbsp;Mengge Zhang,&nbsp;Qi Zhang,&nbsp;Qiupei Liu,&nbsp;Fang Feng,&nbsp;Yan Li,&nbsp;Mengzhen Lai,&nbsp;Haotian Tang,&nbsp;Yi Chen,&nbsp;Meiyu Geng,&nbsp;Wenhu Duan,&nbsp;Jian Ding,&nbsp;Hua Xie","doi":"10.1002/cac2.12521","DOIUrl":"10.1002/cac2.12521","url":null,"abstract":"&lt;p&gt;Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape. Mutations in Kirsten rat sarcoma viral oncogene homolog (&lt;i&gt;KRAS&lt;/i&gt;) and epidermal growth factor receptor (&lt;i&gt;EGFR&lt;/i&gt;) are among the most frequent gain-of-function alterations [&lt;span&gt;1&lt;/span&gt;]. After many years of in-depth research, inhibitors targeting &lt;i&gt;EGFR&lt;/i&gt; or &lt;i&gt;KRAS&lt;/i&gt; mutations have been successfully developed, however, their clinical benefit is relatively limited, and they will inevitably encounter the challenge of drug resistance. The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors. It is worth noting that approved treatment strategies are currently lacking for tumors with different types of &lt;i&gt;KRAS&lt;/i&gt; or &lt;i&gt;EGFR&lt;/i&gt; mutations, including &lt;i&gt;KRAS&lt;sup&gt;G12D&lt;/sup&gt;&lt;/i&gt;, &lt;i&gt;KRAS&lt;sup&gt;G13D&lt;/sup&gt;&lt;/i&gt;, and &lt;i&gt;EGFR&lt;sup&gt;C797S&lt;/sup&gt;&lt;/i&gt; mutations that are common in tumors [&lt;span&gt;2&lt;/span&gt;]. Additionally, oncogene mutations could trigger a cascade of tumor microenvironment changes, ultimately resulting in tumor progression or resistance to programmed death-1 (PD-1) antibody therapy [&lt;span&gt;3, 4&lt;/span&gt;]. SYHA1813, a novel vascular endothelial growth factor receptor (VEGFR) and colony-stimulating factor 1 receptor (CSF1R) dual inhibitor, exhibited potent preclinical anti-glioma activity by inhibiting angiogenesis and promoting tumor immunity and showed promising efficacy in an ongoing clinical study (ChiCTR2100045380) [&lt;span&gt;5, 6&lt;/span&gt;]. Here, we determined SYHA1813's antitumor activity in tumor models bearing &lt;i&gt;KRAS&lt;/i&gt; or &lt;i&gt;EGFR&lt;/i&gt; mutations.&lt;/p&gt;&lt;p&gt;We first examined the effects of SYHA1813 against cell line-derived xenograft (CDX) tumor models containing &lt;i&gt;KRAS&lt;sup&gt;G12C&lt;/sup&gt;&lt;/i&gt; mutation (NCI-H358 lung cancer), &lt;i&gt;KRAS&lt;sup&gt;G12D&lt;/sup&gt;&lt;/i&gt; mutation (PANC-1 pancreatic cancer) and wild-type &lt;i&gt;KRAS&lt;/i&gt; (&lt;i&gt;KRAS&lt;sup&gt;WT&lt;/sup&gt;&lt;/i&gt;) (HT-29 colorectal cancer). The results demonstrated that oral administration of SYHA1813 at a dose of 10 mg/kg significantly reduced tumor growth in the NCI-H358 xenograft model, with comparable efficacy to the US Food and Drug Administration (FDA) approved KRAS&lt;sup&gt;G12C&lt;/sup&gt; inhibitor sotorasib (AMG510) (Figure 1A). SYHA1813 treatment also resulted in tumor regression in PANC-1 and HT-29 xenograft models (Figure 1B-C). No significant body weight loss was observed in all groups (Supplementary Figure S1). Moreover, considering the emergence of drug resistance as a significant challenge of AMG510, we established a drug resistance model of AMG510 (designated as AMG510R). We found that although AMG510 exhibited attenuated efficacy against the AMG510R model compared to the NCI-H358 model, SYHA1813 could still suppress the growth of drug-resistant tumors at the same dose (Figure 1D). Furthermore, SYHA1813 was evaluated in two patient-derived xenograft (PDX) models, including gastric tumor model GC-1-005 (&lt;i&gt;KRAS&lt;sup&gt;G13D&lt;/sup&gt;&lt;/i&gt;) and colorect","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 3","pages":"438-442"},"PeriodicalIF":16.2,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12521","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139711572","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 44, Issue 1","authors":"Monika Raab,&nbsp;Izabela Kostova,&nbsp;Samuel Peña-Llopis,&nbsp;Daniela Fietz,&nbsp;Monika Kressin,&nbsp;Seyed Mohsen Aberoumandi,&nbsp;Evelyn Ullrich,&nbsp;Sven Becker,&nbsp;Mourad Sanhaji,&nbsp;Klaus Strebhardt","doi":"10.1002/cac2.12522","DOIUrl":"https://doi.org/10.1002/cac2.12522","url":null,"abstract":"<p>The cover image is based on the Original Article <i>Rescue of p53 functions by in vitro-transcribed mRNA impedes the growth of highgrade serous ovarian cancer</i> by Monika Raab et al., https://doi.org/10.1002/cac2.12511.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 1","pages":""},"PeriodicalIF":16.2,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12522","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139695464","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":"Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy","authors":"Bin Song,&nbsp;Ping Yang,&nbsp;Shuyu Zhang","doi":"10.1002/cac2.12520","DOIUrl":"10.1002/cac2.12520","url":null,"abstract":"<p>Cancer is a leading cause of death worldwide. Targeted therapies aimed at key oncogenic driver mutations in combination with chemotherapy and radiotherapy as well as immunotherapy have benefited cancer patients considerably. Tumor protein p53 (<i>TP53</i>), a crucial tumor suppressor gene encoding p53, regulates numerous downstream genes and cellular phenotypes in response to various stressors. The affected genes are involved in diverse processes, including cell cycle arrest, DNA repair, cellular senescence, metabolic homeostasis, apoptosis, and autophagy. However, accumulating recent studies have continued to reveal novel and unexpected functions of p53 in governing the fate of tumors, for example, functions in ferroptosis, immunity, the tumor microenvironment and microbiome metabolism. Among the possibilities, the evolutionary plasticity of p53 is the most controversial, partially due to the dizzying array of biological functions that have been attributed to different regulatory mechanisms of p53 signaling. Nearly 40 years after its discovery, this key tumor suppressor remains somewhat enigmatic. The intricate and diverse functions of p53 in regulating cell fate during cancer treatment are only the tip of the iceberg with respect to its equally complicated structural biology, which has been painstakingly revealed. Additionally, <i>TP53</i> mutation is one of the most significant genetic alterations in cancer, contributing to rapid cancer cell growth and tumor progression. Here, we summarized recent advances that implicate altered p53 in modulating the response to various cancer therapies, including chemotherapy, radiotherapy, and immunotherapy. Furthermore, we also discussed potential strategies for targeting p53 as a therapeutic option for cancer.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 3","pages":"297-360"},"PeriodicalIF":16.2,"publicationDate":"2024-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12520","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139689067","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":"AP4 induces JNK1 and a miR-22-3p/FOSL1 feed-forward loop to activate AP-1 and promote colorectal cancer metastasis","authors":"Jinjiang Chou,&nbsp;Markus Kaller,&nbsp;Matjaz Rokavec,&nbsp;Fangteng Liu,&nbsp;Heiko Hermeking","doi":"10.1002/cac2.12514","DOIUrl":"10.1002/cac2.12514","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Colorectal cancer (CRC) is the third most deadly cancer worldwide [&lt;span&gt;1&lt;/span&gt;]. The mortality of CRC has remained high due to limited treatment options for metastatic CRC (mCRC) [&lt;span&gt;2&lt;/span&gt;]. Epithelial-mesenchymal transition (EMT) is an important contributor to mCRC [&lt;span&gt;2&lt;/span&gt;]. The c-MYC proto-oncogene (MYC)-induced transcription factor AP4 (TFAP4/AP4) is a driver of EMT, thereby presumably facilitates mCRC [&lt;span&gt;3, 4&lt;/span&gt;]. The mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) pathway has been implicated in the regulation of EMT and mCRC [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Here, we analyzed whether AP4 regulates components of the MAPK/JNK/AP-1 pathway after MYC activation using CRC cells rendered &lt;i&gt;AP4&lt;/i&gt;-deficient by a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) approach. The detailed methods are shown in the Supplementary file. First, we grouped MYC-induced changes in mRNA expression observed in the CRC cell line DLD-1 &lt;i&gt;AP4&lt;/i&gt; wild-type 1/pRTR-&lt;i&gt;c-MYC&lt;/i&gt;-VSV (&lt;i&gt;AP4&lt;/i&gt;-WT1 DLD-1/pRTR-&lt;i&gt;c&lt;/i&gt;-&lt;i&gt;MYC-&lt;/i&gt;VSV) into 6 non-overlapping expression clusters (Supplementary Figure S1A, left), with cluster 1 representing mRNAs down-regulated, and clusters 2-6 representing different patterns of mRNA up-regulated after MYC activation. MAPK signaling pathway components were strongly over-represented in cluster 6 (Supplementary Figure S1A, right). The AP4 targets &lt;i&gt;MIR22 host gene&lt;/i&gt; (&lt;i&gt;MIR22HG&lt;/i&gt;) and &lt;i&gt;E-&lt;/i&gt;&lt;i&gt;cadherin 1&lt;/i&gt; (&lt;i&gt;CDH1&lt;/i&gt;) were down-regulated after MYC activation in &lt;i&gt;AP4&lt;/i&gt;-WT1 DLD-1/pRTR-&lt;i&gt;c-MYC&lt;/i&gt;-VSV cells (Supplementary Figure S1B). MAPK signaling effectors, including c-&lt;i&gt;Fos proto-oncogene&lt;/i&gt; (&lt;i&gt;FOS&lt;/i&gt;), c-&lt;i&gt;Jun proto-oncogene&lt;/i&gt; (&lt;i&gt;JUN&lt;/i&gt;) and &lt;i&gt;c-J&lt;/i&gt;&lt;i&gt;unB proto-oncogene&lt;/i&gt; (&lt;i&gt;JUNB&lt;/i&gt;), were over-represented in cluster 6. Additional MAPK signaling pathway components. such as &lt;i&gt;c-Jun N-terminal kinase 1&lt;/i&gt; (&lt;i&gt;JNK1&lt;/i&gt;), &lt;i&gt;mitogen-activated protein kinase kinase kinase 1&lt;/i&gt; (&lt;i&gt;MAP3K1&lt;/i&gt;), &lt;i&gt;mitogen-activated protein kinase kinase kinase 13&lt;/i&gt; (&lt;i&gt;MAP3K13&lt;/i&gt;), &lt;i&gt;mitogen-activated protein kinase kinase 3&lt;/i&gt; (&lt;i&gt;MAP2K3&lt;/i&gt;), &lt;i&gt;mitogen-activated protein kinase kinase 7&lt;/i&gt; (&lt;i&gt;MAP2K7&lt;/i&gt;) and &lt;i&gt;FOS&lt;/i&gt;-&lt;i&gt;like&lt;/i&gt; &lt;i&gt;1&lt;/i&gt; (&lt;i&gt;FOSL1&lt;/i&gt;) were found in clusters 3-5 (Supplementary Figure S1B). Interestingly, &lt;i&gt;MAP3K13, MAP2K7, JNK1&lt;/i&gt; and &lt;i&gt;FOSL1&lt;/i&gt; were induced by MYC in an &lt;i&gt;AP4&lt;/i&gt;-dependent manner (Supplementary Figure S1C-D).&lt;/p&gt;&lt;p&gt;Notably, &lt;i&gt;MAP3K13&lt;/i&gt;, &lt;i&gt;FOSL1, JNK1&lt;/i&gt; and &lt;i&gt;MAP2K7&lt;/i&gt; were also up-regulated after activating &lt;i&gt;AP4&lt;/i&gt; for 48 or 72 hours (Figure 1A) and showed AP4-binding sites (CAGCTG) and AP4 occupancy (Supplementary Figure S2A). Therefore, these genes presumably represent direct AP4 targets. MAP3K13 and FOSL1 protein and phosphorylated JNK1 were up-regulated after &lt;i&gt;AP4&lt;/i&gt; activation, whereas JNK1 protein levels remained unch","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 3","pages":"433-437"},"PeriodicalIF":16.2,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472306","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}