Cancer Communications最新文献

{"title":"Reciprocal tumor-platelet interaction through the EPHB1-EFNB1 axis in the liver metastatic niche promotes metastatic tumor outgrowth in pancreatic ductal adenocarcinoma","authors":"Lin-Li Yao,&nbsp;Wei-Ting Qin,&nbsp;Li-Peng Hu,&nbsp;Tie-Zhu Shi,&nbsp;Jian Yu Yang,&nbsp;Qing Li,&nbsp;Hui-Zhen Nie,&nbsp;Jun Li,&nbsp;Xu Wang,&nbsp;Lei Zhu,&nbsp;De-Jun Liu,&nbsp;Yan-Li Zhang,&nbsp;Shu-Heng Jiang,&nbsp;Zhi-Gang Zhang,&nbsp;Xiao-Mei Yang,&nbsp;Dong-Xue Li,&nbsp;Xue-Li Zhang","doi":"10.1002/cac2.12637","DOIUrl":"10.1002/cac2.12637","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The interaction between the metastatic microenvironment and tumor cells plays an important role in metastatic tumor formation. Platelets play pivotal roles in hematogenous cancer metastasis through tumor cell-platelet interaction in blood vessels. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy distinguished by its notable tendency to metastasize to the liver. However, the role of platelet in the liver metastatic niche of PDAC remains elusive. This study aimed to elucidate the role of platelets and their interactions with tumor cells in the liver metastatic niche of PDAC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An mCherry niche-labeling system was established to identify cells in the liver metastatic niche of PDAC. Platelet depletion in a liver metastasis mouse model was used to observe the function of platelets in PDAC liver metastasis. Gain-of-function and loss-of-function of erythropoietin-producing hepatocellular receptor B1 (<i>Ephb1</i>), tumor cell-platelet adhesion, recombinant protein, and tryptophan hydroxylase 1 (<i>Tph1</i>)-knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The mCherry metastatic niche-labeling system revealed the presence of activated platelets in the liver metastatic niche of PDAC patients. Platelet depletion decreased liver metastatic tumor growth in mice. Mechanistically, tumor cell-expressed EPHB1 and platelet-expressed Ephrin B1 (EFNB1) mediated contact-dependent activation of platelets via reverse signaling-mediated AKT signaling activation, and in turn, activated platelet-released 5-HT, further enhancing tumor growth.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We revealed the crosstalk between platelets and tumor cells in the liver metastatic niche of PDAC. Reciprocal tumor-platelet interaction mediated by the EPHB1-EFNB1 reverse signaling promoted metastatic PDAC outgrowth via 5-HT in the liver. Interfering the tumor-platelet interaction by targeting the EPHB1-EFNB1 axis may represent a promising therapeutic intervention for PDAC liver metastasis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"143-166"},"PeriodicalIF":20.1,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12637","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794381","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":"Vascular smooth muscle cell plasticity in the tumor microenvironment","authors":"Caitlin F. Bell,&nbsp;Richard A. Baylis,&nbsp;Nicolas G. Lopez,&nbsp;Wei Feng Ma,&nbsp;Hua Gao,&nbsp;Fudi Wang,&nbsp;Sharika Bamezai,&nbsp;Changhao Fu,&nbsp;Yoko Kojima,&nbsp;Shaunak S. Adkar,&nbsp;Lingfeng Luo,&nbsp;Clint L. Miller,&nbsp;Nicholas J. Leeper","doi":"10.1002/cac2.12635","DOIUrl":"10.1002/cac2.12635","url":null,"abstract":"&lt;p&gt;Smooth muscle cell (SMC) plasticity plays a prominent role in the pathogenesis of multiple diseases. This phenomenon is characterized by the loss of canonical SMC marker gene expression (such as &lt;i&gt;Acta2&lt;/i&gt; and &lt;i&gt;Myh11&lt;/i&gt;), increased proliferation and migration, and the upregulation of genes typically associated with other cell types, such as macrophages [&lt;span&gt;1-3&lt;/span&gt;]. This process is best described in atherosclerosis, where phenotype switching, clonal expansion, and the aberrant expression of inflammatory and matrix proteins contribute to lesion progression and plaque instability [&lt;span&gt;1-4&lt;/span&gt;]. However, this phenomenon has not been studied in the context of tumorigenesis. Here, we investigated whether SMC diversity and plasticity play a role in the tumor microenvironment (TME) using well-established SMC-lineage tracing mouse models, single cell RNA sequencing (scRNA-seq), and in silico ligand-receptor predictions. Detailed study methods are described in the supplementary materials and methods section. The goal of this work was to determine if vascular SMC plasticity should be prioritized as a translational target in oncology.&lt;/p&gt;&lt;p&gt;Two-colored &lt;i&gt;Myh11&lt;/i&gt; lineage tracing mice have native cells that express tdTomato at baseline. Following tamoxifen administration, any cell expressing MYH11 will lose tdTomato and instead express eGFP (Supplementary Figure S1A-B). Syngeneic colon cancers (MC38) implanted subcutaneously into the flanks of these two-colored mice showed a marked and progressive investment of SMCs into the tumor over an 11-day period (Figure 1A-B, Supplementary Figure S1C). High-resolution fluorescent microscopy revealed the loss of the canonical SMC marker ACTA2 in the eGFP&lt;sup&gt;+&lt;/sup&gt; lineage traced cells, indicating that they may have been misidentified using traditional histological approaches (Figure 1C). eGFP&lt;sup&gt;+&lt;/sup&gt; cells were noted far from discernible vasculature within the TME (Figure 1D-E), suggesting their migration away from endothelial networks into the tumor interstitium. Experiments using a separate Rainbow lineage tracer revealed that the expansion of these cells did not occur in a clonal fashion (Supplementary Figure S1D-E) [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To more precisely define the diversity of these cells, scRNA-seq was performed. Unbiased clustering and uniform manifold approximation and projection (UMAP) analysis of the tumor data showed the representation of all anticipated cell types, identified by their gene expression profiles (Supplementary Figure S1F). As expected, eGFP-expressing cells were concentrated in the SMC cluster but were also surprisingly prevalent within the larger macrophage cluster (Figure 1F), representing 10% of eGFP&lt;sup&gt;+&lt;/sup&gt; cells in total. To define the diversity of SMC-derived cells in the TME, all cells expressing an eGFP transcript ≥ 1 were subset and reanalyzed, identifying eight distinct groups of tumor-associated lineage-traced SMCs (Figure 1G). We then used Monocle3 ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"167-171"},"PeriodicalIF":20.1,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794477","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":"SYNCRIP promotes cell cycle progression and lung tumorigenesis by modulating AURKB translation","authors":"Hyeon Ji Kim,&nbsp;Hye Guk Ryu,&nbsp;Mingyu Kang,&nbsp;Namgyu Lee,&nbsp;Hyo-Jin Kim,&nbsp;Dahye Lee,&nbsp;Chaeuk Chung,&nbsp;Sangjune Kim,&nbsp;Kyung-Ha Lee,&nbsp;Wanil Kim,&nbsp;Jin-Seok Byun,&nbsp;Kyong-Tai Kim,&nbsp;Do-Yeon Kim","doi":"10.1002/cac2.12634","DOIUrl":"10.1002/cac2.12634","url":null,"abstract":"&lt;p&gt;Dysregulation of cellular processes, such as cell division and proliferation, is a hallmark of cancer and is driven by the aberrant expression of cell cycle-related genes [&lt;span&gt;1&lt;/span&gt;]. Aurora kinase B (AURKB), due to its pivotal role in mitotic progression, has been implicated in various cancers. Overexpression or hyperactivation of AURKB significantly contributes to tumorigenesis and cancer progression [&lt;span&gt;2&lt;/span&gt;]. Although mechanisms that enhance AURKB activity, including binding to INCENP, autophosphorylation [&lt;span&gt;3&lt;/span&gt;], and ubiquitination by TRAF6 [&lt;span&gt;4&lt;/span&gt;], have been extensively investigated, regulation of AURKB synthesis, particularly mRNA translation, remains unclear. The translation of eukaryotic mRNAs typically occurs either through cap-dependent scanning or through direct ribosomal binding to specialized RNA elements known as internal ribosome entry sites (IRES). IRES-mediated translation is strongly influenced by specific RNA-binding proteins, known as IRES trans-acting factors (ITAFs). SYNCRIP (Synaptotagmin-binding cytoplasmic RNA-interacting protein), also known as hnRNP Q, has been identified as an ITAF [&lt;span&gt;5&lt;/span&gt;], integrating various aspects of RNA metabolism with key cellular processes. Here, we aim to elucidate the mechanism of &lt;i&gt;AURKB&lt;/i&gt; mRNA translation and investigate whether SYNCRIP regulates &lt;i&gt;AURKB&lt;/i&gt; mRNA translation in lung cancer.&lt;/p&gt;&lt;p&gt;To investigate the mechanisms underlying &lt;i&gt;AURKB&lt;/i&gt; mRNA translation, we analyzed AURKB protein levels following treatment with rapamycin, an inhibitor of eIF4E-mediated cap-dependent translation, and cycloheximide (CHX), an inhibitor of the elongation phase of translation. Treatment with CHX significantly reduced AURKB protein production, whereas rapamycin had no effect, suggesting that &lt;i&gt;AURKB&lt;/i&gt; can be translated via a cap-independent mechanism (Figure 1A, Supplementary Figure S1A-B). To further validate this finding, we used a bicistronic reporter containing the 5′-UTR of &lt;i&gt;AURKB&lt;/i&gt; mRNA positioned between the coding sequences for Renilla (RLUC) and Firefly (FLUC) luciferases (Supplementary Figure S1C). This experiment confirmed that the &lt;i&gt;AURKB&lt;/i&gt; 5’-UTR facilitates translation of a downstream cistron in a cap-independent manner (Figure 1B, Supplementary Figure S1D).&lt;/p&gt;&lt;p&gt;We next examined the correlation between AURKB and SYNCRIP protein expression in human lung cancer tissues. Utilizing the LinkedOmics database, we identified 11,466 genes associated with SYNCRIP in lung adenocarcinoma (LUAD) and 11,928 genes in lung squamous cell carcinoma (LSCC) (Supplementary Figure S2A-B) [&lt;span&gt;6&lt;/span&gt;]. Gene set enrichment analysis revealed a strong positive correlation between AURKB and SYNCRIP in both LUAD and LSCC (Supplementary Figure S2C-G). Additionally, immunoblot analysis revealed higher expression levels of both proteins in tumor tissues compared to adjacent normal tissues (Figure 1C). We further validated the correlation between these prot","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"138-142"},"PeriodicalIF":20.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12634","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784255","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":"Nicotinamide N-methyltransferase negatively regulates metastasis-promoting property of cancer-associated fibroblasts in lung adenocarcinoma","authors":"Peiyu Wang,&nbsp;Guangxi Wang,&nbsp;Haoran Li,&nbsp;Yuyao Yuan,&nbsp;Haiming Chen,&nbsp;Shaodong Wang,&nbsp;Zewen Sun,&nbsp;Fanjie Meng,&nbsp;Yun Li,&nbsp;Fan Yang,&nbsp;Jun Wang,&nbsp;Kezhong Chen,&nbsp;Mantang Qiu","doi":"10.1002/cac2.12633","DOIUrl":"10.1002/cac2.12633","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;Recurrence and metastasis remain significant challenges in lung adenocarcinoma (LUAD) after radical resection. The mechanisms behind the recurrence and metastasis of LUAD remain elusive, and deregulated cellular metabolism is suspected to play a significant role. This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase (NNMT) in LUAD.&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;Untargeted metabolomic analyses were performed to detect metabolism irregularities. Single-cell RNA sequencing (RNA-seq) databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment. The biological functions of NNMT were investigated both in vitro and in vivo, with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms. Finally, single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.&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;Untargeted metabolomic analyses revealed metabolic aberrations in amino acids, organic acids, lipids, and nicotinamide pathways, which are linked to metastasis of non-small cell lung cancer. NNMT is a key enzyme in nicotinamide metabolism, and we found the bulk tissue mRNA level of &lt;i&gt;NNMT&lt;/i&gt; gene was inversely associated with LUAD metastasis. NNMT was proved to be predominantly expressed in cancer-associated fibroblasts (CAFs) within the stromal regions of LUAD, and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD. The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments, which confirmed that NNMT negatively regulated the metastasis-promoting properties of CAFs in LUAD. Mechanistically, the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle, resulting in heightened methylation at H3K4me3. This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs, including those encoding collagens, integrins, laminins, and matrix metalloproteinases, thereby facilitating cancer cell invasion and metastasis. Reanalysis of single-cell RNA-seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT's negative regulation of these genes in CAFs.&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;This study provides novel insights into the metabolic and epigenetic regulatory ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"110-137"},"PeriodicalIF":20.1,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12633","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766580","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":"Advances in cervical cancer: current insights and future directions","authors":"Miaochun Xu,&nbsp;Canhui Cao,&nbsp;Peng Wu,&nbsp;Xiaoyuan Huang,&nbsp;Ding Ma","doi":"10.1002/cac2.12629","DOIUrl":"10.1002/cac2.12629","url":null,"abstract":"<p>In alignment with the World Health Organization's strategy to eliminate cervical cancer, substantial progress has been made in the treatment of this malignancy. Cervical cancer, largely driven by human papillomavirus (HPV) infection, is considered preventable and manageable because of its well-established etiology. Advancements in precision screening technologies, such as DNA methylation triage, HPV integration detection, liquid biopsies, and artificial intelligence-assisted diagnostics, have augmented traditional screening methods such as HPV nucleic acid testing and cytology. Therapeutic strategies aimed at eradicating HPV and reversing precancerous lesions have been refined as pivotal measures for disease prevention. The controversy surrounding surgery for early-stage cervical cancer revolves around identifying optimal candidates for minimally invasive and conservative procedures without compromising oncological outcomes. Recent clinical trials have yielded promising results for the development of systemic therapies for advanced cervical cancer. Immunotherapies, such as immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and targeted therapy have demonstrated significant effectiveness, marking a substantial advancement in cervical cancer management. Various combination therapies have been validated, and ongoing trials aim to enhance outcomes through the development of novel drugs and optimized combination regimens. The prospect of eradicating cervical cancer as the first malignancy to be eliminated is now within reach. In this review, we provide a comprehensive overview of the latest scientific insights, with a particular focus on precision managements for various stages of cervical disease, and explore future research directions in cervical cancer.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"77-109"},"PeriodicalIF":20.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12629","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749557","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":"PTPN9 regulates HER3 phosphorylation during trastuzumab treatment and loss of PTPN9 is a potential biomarker for trastuzumab resistance in HER2 positive breast cancer","authors":"Abul Azad,&nbsp;Maryam Arshad,&nbsp;Daniele Generali,&nbsp;Katharina Feldinger,&nbsp;Merel Gijsen,&nbsp;Carla Strina,&nbsp;Mariarosa Cappelletti,&nbsp;Daniele Andreis,&nbsp;Russell Leek,&nbsp;Syed Haider,&nbsp;Pirkko-Liisa Kellokumpu-Lehtinen,&nbsp;Ioannis Roxanis,&nbsp;Adrian Llewellyn Harris,&nbsp;Abeer Mahmoud Shaaban,&nbsp;Heikki Joensuu,&nbsp;Anthony Kong","doi":"10.1002/cac2.12632","DOIUrl":"10.1002/cac2.12632","url":null,"abstract":"&lt;p&gt;Although trastuzumab does not bind to human epidermal growth factor receptor 3 (HER3), it dephosphorylates HER3 through a previously unknown mechanism. In addition, HER3 is reactivated during prolonged trastuzumab treatment and upon resistance [&lt;span&gt;1&lt;/span&gt;]. Previous study showed that tyrosine-protein phosphatase non-receptor type 9 (PTPN9) inhibits STAT3/STAT5 signalling by dephosphorylation of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in breast cancer [&lt;span&gt;2&lt;/span&gt;], but how this would affect HER3 was not analyzed especially in relation to trastuzumab treatment. We investigated the role of PTPN9 in HER3 signaling in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. The materials and methods applied in this research were described in the supplementary materials.&lt;/p&gt;&lt;p&gt;We showed that PTPN9 was upregulated after trastuzumab treatment in both SKBR3 and BT474 cells (Figure 1A), but this is not the case for two other PTPs which are known to regulate EGFR and HER2 respectively, PTP1B and PTPN13 [&lt;span&gt;3, 4&lt;/span&gt;] (Supplementary Figure S1A). The upregulation of PTPN9 occurred concomitantly with a decrease in the phosphorylation of HER3 and its downstream effector protein kinase B (PKB or Akt), but not HER2 and EGFR (Figure 1A and Supplementary Figure S1B). Moreover, HER3 and Akt were reactivated in trastuzumab-resistant SKBR3 and BT474 cells with a concomitant decreased PTPN9 expression. In contrast, EGFR and HER2 phosphorylation was not decreased by trastuzumab treatment but was further increased during trastuzumab resistance, which was previously shown to be due to a disintegrin and metalloproteinase 10/17 (ADAM10/17) mediated HER ligand activation [&lt;span&gt;1, 5&lt;/span&gt;]. In immunofluorescence studies, PTPN9 expression was upregulated in cytoplasm and co-localized with the cytoplasmic HER3 following trastuzumab treatment for 4 hours in both SKBR3 and BT474 cells (Supplementary Figure S1C), correlated with a decrease of pHER3 seen in the western blot at this time point. PTPN9 expression was decreased again in trastuzumab-resistant BT474 and SKBR3 cells (Supplementary Figure S1C) which was correlated with a reactivation of HER3. Similarly, PTPN9 expression and pHER3 levels were seen to be inversely correlated during trastuzumab treatment in MDA-MB-453 and MDA-MB-361 cells (Supplementary Figure S1D). In relation to other anti-HER2 therapies, trastuzumab and ado-trastuzumab emtansine (T-DM1) (and to much lesser extent for trastuzumab deruxtecan [TDxd] but not neratinib and pertuzumab monotherapy) could increase PTPN9 expression (Supplementary Figure S1E), although decreased HER3 and Akt phosphorylation was seen in all drugs, which may reflect the different mechanisms of action of these drugs. The trastuzumab-based combination treatment also upregulated PTPN9 expression with concomitant decrease in HER3 and Akt phosphorylation (Supplementary Figure S1E).&lt;/p&gt;&lt;p&gt;Next, we ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"68-73"},"PeriodicalIF":20.1,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709188","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":"Ex vivo STAT3 phosphorylation in circulating immune cells: a novel biomarker for early cancer diagnosis and response to anti-PD-1 therapy","authors":"Sung-Woo Lee,&nbsp;Young Ju Kim,&nbsp;Saei Jeong,&nbsp;Kyung Na Rho,&nbsp;Jeong Eun Noh,&nbsp;Hee-Ok Kim,&nbsp;Hyun-Ju Cho,&nbsp;Yoo Duk Choi,&nbsp;Deok Hwan Yang,&nbsp;Eu Chang Hwang,&nbsp;Woo Kyun Bae,&nbsp;Sook Jung Yun,&nbsp;Ju Sik Yun,&nbsp;Cheol-Kyu Park,&nbsp;In-Jae Oh,&nbsp;Jae-Ho Cho","doi":"10.1002/cac2.12631","DOIUrl":"10.1002/cac2.12631","url":null,"abstract":"&lt;p&gt;Basal signal transducer and activator of transcription 3 (STAT3) activation is well-documented in the tumor microenvironment (TME) due to its association with cancer prognosis [&lt;span&gt;1&lt;/span&gt;]. However, its presence and clinical relevance in the bloodstream remain unexplored. Given that STAT3-inducing cytokines, such as interleukin-6 (IL-6), are often elevated in the bloodstream of various cancer patients [&lt;span&gt;2, 3&lt;/span&gt;], we aimed to investigate basal STAT3 activation in blood by developing a methodology to assess &lt;i&gt;ex vivo&lt;/i&gt; phosphorylation of STAT3 (pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt;) in circulating immune cells.&lt;/p&gt;&lt;p&gt;Since phosphorylation is a transient process prone to dephosphorylation, we sought to minimize the time between blood collection and the experiment. Specifically, 1) we limited the use of peripheral blood mononuclear cell (PBMC) samples to those processed within 1 hour of blood collection, and 2) immediately fixed the samples after thawing (Figure 1A). Notably, 135 non-small cell lung cancer (NSCLC) patient samples processed in this way exhibited significantly higher levels of pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt;-positive cells compared to healthy controls (Figure 1B and Supplementary Table S1). Prolonged handling and extended experimental steps significantly decreased pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; expression (Supplementary Figure S1), underscoring the importance of our novel approach in controlling the time between blood collection and the experiment.&lt;/p&gt;&lt;p&gt;We next investigated the cell types within PBMCs that express pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt;. CD4&lt;sup&gt;+&lt;/sup&gt; T cells exhibited the highest pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; expression, followed by CD8&lt;sup&gt;+&lt;/sup&gt; T cells, whereas monocytes, B cells, and natural killer (NK) cells showed minimal pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; expression (Figure 1C). Within both CD4&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt; T cells, pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; expression was highest in the least differentiated CD27&lt;sup&gt;+&lt;/sup&gt; CD45RA&lt;sup&gt;+&lt;/sup&gt; naïve subset (Figure 1C) [&lt;span&gt;4&lt;/span&gt;]. A similar pattern was observed across multiple other cancer types (Figure 1D and Supplementary Figure S2).&lt;/p&gt;&lt;p&gt;Focusing on CD4&lt;sup&gt;+&lt;/sup&gt; naïve T cells, pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; expression showed a stark contrast between NSCLC patients and healthy donors, even at stage I (Figure 1E). The area under the receiver operating characteristic curve for distinguishing stage I NSCLC patients from healthy donors was 0.9851, with a sensitivity of 0.92 at 95% specificity (Figure 1F). No tumor-specific or patient-specific clinical variables correlated with pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; expression in NSCLC patients (Supplementary Figure S3), while surgical removal of the tumor decreased pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; expression (Figure 1G), supporting a direct association between pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; and tumor burden. These findings underscore the potential of pSTAT3&lt;i&gt;&lt;sup&gt;ex vivo&lt;/sup&gt;&lt;/i&gt; as a blood-","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"58-62"},"PeriodicalIF":20.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680963","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":"Anti-tumor drug supervision in China from 2010 to 2024: the evolution and prospect of drug review standards","authors":"Ling Tang,&nbsp;Yuanyuan Song,&nbsp;Hong Zhang,&nbsp;Ruimin Hao,&nbsp;Xin Tong,&nbsp;Xing Ai,&nbsp;Jun Ma,&nbsp;Zhimin Yang","doi":"10.1002/cac2.12630","DOIUrl":"10.1002/cac2.12630","url":null,"abstract":"&lt;p&gt;Over the past decade, the research and development (R&amp;D) of anti-tumor drugs in China has undergone a remarkable leap, maintaining a high level of motivation.&lt;/p&gt;&lt;p&gt;With respect to pharmaceutical R&amp;D paradigms in China, the domestic market was once dominated by generic drugs. A progressive transition towards the development of innovative pharmaceuticals is emerging, consequent to the reforms in drug evaluation and approval mechanisms and the promotion of novel drug development in China. The introduction of new drugs from other countries to China used to lag behind. Now a progressive approach is being taken towards synchronization in global R&amp;D. The emergence of new players in the pharmaceutical industry and the enhancement of corporate R&amp;D competencies have further facilitated the internationalization of China's drug R&amp;D endeavors. The rapid advancement in pharmaceutical R&amp;D has significantly enhanced China's drug regulatory capabilities. In August 2015, the State Council of the People's Republic of China promulgated the “&lt;i&gt;Opinions on Reforming the Approval Procedures for Drugs and Medical Devices&lt;/i&gt;” marking the official commencement of reforms in the drug evaluation and approval system. The Chinese drug regulatory authorities are integrating resources and optimizing drug review processes through the development of a scientifically complete system of Good Review Practice.&lt;/p&gt;&lt;p&gt;Innovative drugs, including new drugs, improved new drugs (those improved formulations or dose forms with existing active ingredients), biosimilars, and domestic generic drugs with unimported original drugs, constitute essential assurances for patients in China and offer better accessibility of medications. To better understand the changes since the inception of the drug evaluation and approval reforms in 2015, we have collected data on new drug applications (NDAs) for the aforementioned types of drugs submitted to the Center for Drug Evaluation (CDE) under the National Medical Products Administration (NMPA) in China, spanning from January 2010 to March 2024.&lt;/p&gt;&lt;p&gt;A total of 374 NDAs for anti-tumor drugs had been approved from January 1, 2010 to March 31, 2024, including 186 (49.7%) imported drugs and 188 (50.3%) domestic drugs. The domestic drugs included 139 (37.1%) innovative/improved new drugs, 31 (8.3%) generic drugs, and 18 (4.8%) biosimilars, respectively.&lt;/p&gt;&lt;p&gt;Before 2018, China's pharmaceutical market mainly relied on domestic generic drugs. However, since 2018, the number of drug authorizations granted to innovative drugs has been on the rise, with a notable increase in domestically developed innovative drugs (Figure 1). The emergence of an upward trend in domestically R&amp;D innovative drugs is due to better regulatory frameworks, faster review processes, and the introduction of technical standards. The Chinese government has implemented policies promoting anti-tumor drug R&amp;D, including priority review, conditional approval,","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"63-67"},"PeriodicalIF":20.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675158","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 IL-17A to manage immunotherapy-induced toxicity in melanoma","authors":"Kai Huang","doi":"10.1002/cac2.12628","DOIUrl":"10.1002/cac2.12628","url":null,"abstract":"&lt;p&gt;The landscape of cancer treatment has been dramatically transformed by the advent of immune checkpoint inhibitors (ICIs), particularly in the management of advanced melanoma. However, despite their revolutionary success, the use of ICIs is often complicated by immune-related adverse events (irAEs), which can range from mild symptoms to severe, life-threatening conditions. Understanding the underlying mechanisms of these toxicities is crucial to enhancing the safety and effectiveness of immunotherapy [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In a recent study published in &lt;i&gt;Nature Cancer&lt;/i&gt;, Dimitriou &lt;i&gt;et al.&lt;/i&gt; [&lt;span&gt;2&lt;/span&gt;] provide novel insights into the immunological processes driving irAEs in melanoma patients treated with ICIs. The researchers identified a significant increase in interleukin-17A (IL-17A) expressing CD4&lt;sup&gt;+&lt;/sup&gt; T cells at the onset of irAEs, pointing to a type III immune response as a key factor in these adverse events. This discovery not only deepens our understanding of irAEs but also suggests a potential therapeutic target for mitigating these toxicities without compromising the antitumor efficacy of ICIs.&lt;/p&gt;&lt;p&gt;What sets these findings apart is their contribution to a broader understanding of the mechanisms behind ICIs’ AEs compared to primary autoimmune diseases. While irAEs share certain immune mechanisms with autoimmune diseases, such as rheumatoid arthritis or psoriasis, the immunological context of ICIs is distinct because of the pharmacological disruption of immune checkpoints [&lt;span&gt;3&lt;/span&gt;]. The study highlights the difference between irAEs and primary autoimmune disease by showing that IL-17A expressing CD4&lt;sup&gt;+&lt;/sup&gt; T cells are particularly implicated in ICI-induced toxicity, which is not a prominent feature of many primary autoimmune conditions.&lt;/p&gt;&lt;p&gt;The study utilized a comprehensive approach, including proteomic analyses, multiplex cytokine and chemokine assays, and flow cytometry, to examine the immune profiles of melanoma patients undergoing ICI therapy. A critical finding was the consistent upregulation of IL-17A, along with other type I and III cytokines, at the onset of irAEs. These results were corroborated by the observation that IL-17A expressing CD4&lt;sup&gt;+&lt;/sup&gt; T cells were significantly elevated in patients experiencing irAEs compared to those who did not.&lt;/p&gt;&lt;p&gt;Importantly, the authors provided proof-of-principle evidence for the therapeutic potential of targeting IL-17A in managing irAEs. In a small cohort of patients with severe, corticosteroid-refractory irAEs, treatment with the anti-IL-17A monoclonal antibody secukinumab led to a resolution of symptoms. Secukinumab, primarily used in the treatment of psoriasis, where IL-17A plays a well-established pathogenic role, offers a novel therapeutic option for managing irAEs [&lt;span&gt;4&lt;/span&gt;]. Its efficacy in these patients not only underscores the importance of IL-17A in both conditions but also suggests that treatment strategies from autoimmune dise","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"56-57"},"PeriodicalIF":20.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615171","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":"Epigenomic exploration of disease status of EGFR-mutated non-small cell lung cancer using plasma cell-free DNA hydroxymethylomes","authors":"Yong Peng,&nbsp;Jason Karpus,&nbsp;Jyoti D. Patel,&nbsp;Everett E. Vokes,&nbsp;Marina Chiara Garassino,&nbsp;Kirsteen Lugtu,&nbsp;Zhou Zhang,&nbsp;Wei Zhang,&nbsp;Mengjie Chen,&nbsp;Chuan He,&nbsp;Christine M. Bestvina","doi":"10.1002/cac2.12606","DOIUrl":"10.1002/cac2.12606","url":null,"abstract":"&lt;p&gt;Non-small cell lung cancer (NSCLC) represents about 85% of histological diagnoses of lung cancer [&lt;span&gt;1&lt;/span&gt;]. Epidermal growth factor receptor (&lt;i&gt;EGFR&lt;/i&gt;) mutations occur in 12.7%-40.3% of NSCLC [&lt;span&gt;2&lt;/span&gt;], and 5-hydroxymethylcytosine (5hmC) signatures and pathways can be inhibited by EGFR signaling [&lt;span&gt;3&lt;/span&gt;]. The epigenome of plasma cell-free DNA (cfDNA), including 5hmC, has demonstrated promise as a cancer biomarker [&lt;span&gt;4&lt;/span&gt;]. Currently, it remains unknown whether cfDNA 5hmC can identify disease status of NSCLC. Here, we performed 5hmC Seal-sequencing of 302 plasma cfDNA samples from 113 patients with metastatic &lt;i&gt;EGFR&lt;/i&gt;-mutated NSCLC, which included 240 samples reflecting stable disease (SD) and 62 samples reflecting progressive disease (PD) (Figure 1A, Supplementary Table S1). SD and PD were clinically defined by the treating physician (Supplementary Methods).&lt;/p&gt;&lt;p&gt;High quality was ensured, 11 samples as outliers were discarded, and batch effects were removed effectively (Supplementary Figures S1, Supplementary Tables S2-S3). The remaining 291 samples were classified by disease status and various potential confounding factors (Figure 1A, Supplementary Tables S4-S7). The relative frequency of disease status in each group was nearly identical to that of the overall 291 samples (Supplementary Figure S4). cfDNA 5hmC peaks of each sample displayed proper reproducibility (Supplementary Figure S5A). Interestingly, 123 cfDNA 5hmC peaks were located on the &lt;i&gt;EGFR&lt;/i&gt; gene (Supplementary Figure S5B, Supplementary Table S8). Genomewide cfDNA 5hmC levels were overall similar between PD and SD samples, as well as various potential confounders (Supplementary Figures S5C-E and S6).&lt;/p&gt;&lt;p&gt;A substantial portion of 5hmC peaks displayed high heterogeneity of 5hmC levels among the 291 samples (Supplementary Figure S7A), which were not derived from disease status and potential confounders (Supplementary Figure S7B-E, Supplementary Table S9). With 1,000 bp bins instead of peaks, similar results were observed (Supplementary Figure S8). We found that &lt;i&gt;EGFR&lt;/i&gt; mutations were associated with 5hmC heterogeneity (Supplementary Figure S9A) and identified 4,743 cfDNA 5hmC peaks (Supplementary Table S10) with 5hmC levels differing among intergroups of &lt;i&gt;EGFR&lt;/i&gt; mutation subtypes more than that of intragroups (&lt;i&gt;P&lt;/i&gt; &lt; 0.005) (Supplementary Figure S9B). Interestingly, the 4,743 cfDNA 5hmC peaks were strongly associated with the function of &lt;i&gt;EGFR&lt;/i&gt; (Supplementary Figure S10A), but not associated with disease status (Supplementary Figure 10B-E). This result was further confirmed by a nearly identical 5hmC level between PD and SD samples (Supplementary Figure 10F), as well as distribution of false discovery rate and &lt;i&gt;P&lt;/i&gt; values (Figure 1B).&lt;/p&gt;&lt;p&gt;Disease status-associated 5hmC peaks were completely different from potential confounder-associated 5hmC peaks, except for smoking status (Supplementary Figure S11). Consistently, 5","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"51-55"},"PeriodicalIF":20.1,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615168","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}