Cancer Communications最新文献_第5页

Neoadjuvant HER2 inhibition induces ESR1 DNA methylation alterations resulting in clinically relevant ER expression changes in breast cancers 新辅助HER2抑制诱导ESR1 DNA甲基化改变，导致乳腺癌中临床相关的ER表达改变。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-12-15 DOI: 10.1002/cac2.12640

Gavin P. Dowling, Gordon R. Daly, Aisling Hegarty, Michael Flanagan, Mihaela Ola, Ramón Fallon, Sinéad Cocchiglia, Vikrant Singh, Katherine M. Sheehan, Fiona Bane, Jason McGrath, Louise Watson, Sandra Hembrecht, Bryan Hennessy, Patrick G. Morris, Arnold D. K. Hill, Damir Varešlija, Leonie S. Young

The expression of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) in breast cancer can change in response to treatment and pivotally influence tumor behavior and clinical management [1]. Receptor discordance has been observed at various distant metastatic site (bone, lung, liver, and brain), with a routine loss of ER and gains in HER2 reported [2]. This receptor discordance can influence tumor responsiveness to both HER2 inhibitor and endocrine therapies. Although the mechanisms underlying receptor expression changes are not fully understood, we recently reported gains in ESR1 promoter hypermethylation as a potential driver of ER loss during disease progression [3]. In this study, mechanisms underlying altered receptor expression and associated disease outcomes were examined following neoadjuvant trastuzumab treatment.We investigated the impact of HER2 inhibition on ER expression. From a cohort of 2,917 patients, 527 tumors were HER2-positive. Of these, 161 patients received neoadjuvant trastuzumab with systemic chemotherapy (Supplementary Figure S1, Supplementary Table S1). In this cohort (n = 161), 89 patients (55.3%) achieved pathological complete response (pCR), while 72 patients (44.7%) had residual disease, and 18 patients developed metastases (Clinical Cohort, Figure 1A, Supplementary Table S1). A statistically significant higher proportion of patients with ER-negative tumors achieved pCR compared to their ER-positive counterparts (P = 0.016, Supplementary Table S1), consistent with previous studies [4]. In patients with residual disease, the most notable finding was the observed gain of ER protein expression and loss of HER2 in a number of patients (33% and 17%, respectively; Figure 1B). ER protein status remained unchanged in 38 patients (53%), with a loss of ER observed in 8 patients (11%) (Figure 1B).Epigenetic modifications are a potential mechanism underlying this observed receptor discordance. In this study, the role of DNA methylation in altered receptor expression was investigated (DNA methylation cohort, Figure 1A). Global DNA methylation was assessed in pre- and post-treatment samples (n = 16; Supplementary Table S2), of which 7 patient tumors were matched (biopsy and resection). Differentially methylated gene (DMG) analysis segregated patient tumors into pre- or post-treatment groups, illustrating the dominance of hypomethylation in post-treatment patient tumors (Figure 1C). Notably, pathway analysis identified Estrogen Response Early, Epithelial Mesenchymal Transition (EMT), ERRB, AMPK, and RAS signaling (P < 0.05) as statistically significant pathways (Supplementary Figure S2A-B). Network graph analysis revealed Estrogen Response Early, Estrogen Response Late and EMT as hub pathways (Figure 1D). Estrogen-responsive genes such as

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引用次数: 0

Cancer situation in China: an analysis based on the global epidemiological data released in 2024 中国癌症状况：基于2024年全球流行病学数据的分析

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-12-10 DOI: 10.1002/cac2.12627

Xiayao Diao, Chao Guo, Yukai Jin, Bowen Li, Xuehan Gao, Xin Du, Zhenchong Chen, Minju Jo, Yi Zeng, Chao Ding, Wenwu Liu, Jianrong Guo, Shanqing Li, Haibo Qiu

Background

Cancer remains a major cause of mortality and a significant economic burden in China. Exploring the disparities in cancer patterns and control strategies between China and developed countries may offer valuable insights for policy formulation and enhance cancer management efforts. This study examined the incidence, mortality, and disability-adjusted life year (DALY) burden of cancer in China, and compared these metrics with those observed in the United States (US) and the United Kingdom (UK).

Methods

Data on cancer incidence, mortality, and DALYs for China, the US, and the UK were sourced from the GLOBOCAN 2022 online database and the Global Burden of Disease 2021 study (GBD 2021). We utilized Joinpoint regression models to analyze trends in cancer incidence and mortality across these countries, calculating annual percent changes (APCs) and determining the optimal joinpoints.

Results

In 2022, China recorded around 4,824,703 new cancer cases and 2,574,176 cancer-related deaths, contributing to 71,037,170 DALYs. China exhibited a lower cancer incidence rate compared to the US and the UK. Although cancer-related mortality in China is slightly lower than that in the UK, it is significantly higher than that in the US. Additionally, China experienced significantly higher DALY rates compared to both the US and UK. The cancer landscape in China was also undergoing significant changes, with a rapid rise in the incidence and burden of lung, colorectal, breast, cervical, and prostate cancers. Meanwhile, the incidence and burden of stomach cancer continued to decline. Although the incidence of liver and esophageal cancers was decreasing, the burden of liver cancer was increasing, while the burden of esophageal cancer remained largely unchanged.

Conclusions

The cancer profile of China is shifting from that of a developing country to one more typical of a developed country. The ongoing population aging and the rise in unhealthy lifestyles are expected to further escalate the cancer burden in China. Consequently, it is crucial for Chinese authorities to revise the national cancer control program, drawing on successful strategies from developed countries, while also accounting for the regional diversity in cancer types across China.

背景：在中国，癌症仍然是导致死亡的主要原因，也是一个重要的经济负担。探讨中国与发达国家在癌症模式和控制策略上的差异，可以为政策制定和加强癌症管理工作提供有价值的见解。本研究调查了中国癌症的发病率、死亡率和残疾调整生命年（DALY）负担，并将这些指标与美国和英国的观察结果进行了比较。方法：中国、美国和英国的癌症发病率、死亡率和DALYs数据来自GLOBOCAN 2022在线数据库和全球疾病负担2021研究（GBD 2021）。我们利用连接点回归模型分析了这些国家癌症发病率和死亡率的趋势，计算了年变化百分比（apc）并确定了最佳连接点。结果：2022年，中国记录了约4,824,703例新发癌症病例和2,574,176例癌症相关死亡，贡献了71,037,170 DALYs。与美国和英国相比，中国的癌症发病率较低。虽然中国的癌症相关死亡率略低于英国，但明显高于美国。此外，与美国和英国相比，中国的DALY率要高得多。中国的癌症格局也发生了重大变化，肺癌、结直肠癌、乳腺癌、宫颈癌和前列腺癌的发病率和负担迅速上升。同时，胃癌的发病率和负担持续下降。虽然肝癌和食管癌的发病率在下降，但肝癌的负担在增加，食管癌的负担基本保持不变。结论：中国的癌症状况正在从一个发展中国家转变为一个更典型的发达国家。持续的人口老龄化和不健康生活方式的增加预计将进一步加剧中国的癌症负担。因此，至关重要的是，中国当局要修改国家癌症控制计划，借鉴发达国家的成功战略，同时也要考虑到中国癌症类型的地区多样性。

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引用次数: 0

The interplay between natural killer cells and pancreatic stellate cells in pancreatic ductal adenocarcinoma 胰腺导管腺癌中自然杀伤细胞与胰腺星状细胞的相互作用。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-12-09 DOI: 10.1002/cac2.12638

Rachel Elizabeth Ann Fincham, Parthiban Periasamy, Craig Ryan Joseph, Jia Meng, Jeffrey Chun Tatt Lim, Felicia Wee, Konstantinos Stasinos, Michelle Rodrigues Goulart, Jiangfeng Ye, Li Yen Chong, Bijin Veonice Au, Denise Goh, Joe Poh Sheng Yeong, Hemant Mahendrakumar Kocher

Pancreatic ductal adenocarcinoma (PDAC) remains one of medicine's most urgent areas of unmet need. With 5-year survival rates of ∼11%, PDAC is set to become the second leading cause of cancer related deaths by 2040 [1]. The complex tumour microenvironment (TME) in PDAC, responsible for poor prognosis, is comprised of extracellular matrix (ECM) proteins and multiple cell types; with pancreatic stellate cells (PSCs), which become activated cancer associated fibroblasts (CAFs), being regarded as key orchestrators of the TME. We have demonstrated that treatment with all-trans retinoic acid (ATRA) can render activated PSCs (aPSC) to a quiescent (qPSC) phenotype (shift to G1 phase of cell cycle and other features [2]), resulting in stromal remodelling and thus, influencing cancer cell co-targeting with chemotherapy in patients [3]. This has resulted in the use of ATRA along with standard-of-care chemotherapy in the Stromal TARgeting for PAncreatic Cancer (STARPAC) clinical trial, with promising results [4]. These clinically relevant [5], exciting potential therapeutic benefits of stromal co-targeting through rendering PSCs quiescent [6], along with predictive inflammation-related biomarkers [7], and increased focus on cellular therapeutics such as NK cells, led us to postulate potential targetable PSC-immune cell interactions which may uncover a comprehensive therapeutic strategy for treating hitherto, incurable PDAC.We identified differential NK-92 (a cell line representing NK cells) cytotoxicity against qPSCs (telomerase reverse transcriptase (hTERT) immortalised PS1 cell line rendered quiescent by administering ATRA for seven days at 1 µmol/L daily [2]) and aPSC phenotypes as assessed by surface expression of CD107a/b, and Calcein Acetyoxymethyl (AM) cytotoxicity assays (Supplementary Figure S1A-B). Furthermore, qPSC or aPSC education of NK-92 cells resulted in altered and distinct cytotoxicity towards pancreatic cancer cells (BxPC3, Capan2, MiaPaca2) as indicated by surface CD107a/b expression (Figure 1A) and complemented by Calcein AM cytotoxicity assays (data not shown).Surface and intracellular markers for CAF subtypes (pCAFassigner subtypes A-D [3]; CD105+/− CAFs [8]) and surface activating/inhibitory receptors and intracellular functional markers for NK cells, as assessed by spectral flow cytometry and Luminex ELISA secretome analysis, demonstrated that this interaction is, indeed, bidirectional. We demonstrated stellate cell polarisation to a myofibroblastic activation state [2] in response to direct contact with NK cells as assessed by alpha-SMA abundance (geometric mean fluorescence intensity (MFI)), as well as upregulation of CD105 expression, a CAF marker of anti-tumour immunity [8], irrespective of previous PSC activation status (Figure 1B), a fact not obse

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引用次数: 0

Reciprocal tumor-platelet interaction through the EPHB1-EFNB1 axis in the liver metastatic niche promotes metastatic tumor outgrowth in pancreatic ductal adenocarcinoma 肝转移生态位中通过EPHB1-EFNB1轴的肿瘤-血小板相互作用促进胰腺导管腺癌转移性肿瘤的生长。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-12-08 DOI: 10.1002/cac2.12637

Lin-Li Yao, Wei-Ting Qin, Li-Peng Hu, Tie-Zhu Shi, Jian Yu Yang, Qing Li, Hui-Zhen Nie, Jun Li, Xu Wang, Lei Zhu, De-Jun Liu, Yan-Li Zhang, Shu-Heng Jiang, Zhi-Gang Zhang, Xiao-Mei Yang, Dong-Xue Li, Xue-Li Zhang

Background

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.

Methods

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 (Ephb1), tumor cell-platelet adhesion, recombinant protein, and tryptophan hydroxylase 1 (Tph1)-knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.

Results

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.

Conclusion

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.

背景：转移性微环境与肿瘤细胞的相互作用在转移性肿瘤的形成中起着重要作用。血小板通过血管中肿瘤细胞与血小板的相互作用在血行性肿瘤转移中起关键作用。胰腺导管腺癌（PDAC）是一种高度致死性的恶性肿瘤，其显著的特点是易于转移到肝脏。然而，血小板在PDAC肝转移生态位中的作用仍然难以捉摸。本研究旨在阐明血小板在PDAC肝转移生态位中的作用及其与肿瘤细胞的相互作用。方法：建立mCherry小生境标记系统，鉴定PDAC肝转移小生境细胞。采用小鼠肝转移模型，观察血小板在PDAC肝转移中的作用。利用促红细胞生成素产生肝细胞受体B1 （Ephb1）的功能获得和功能丧失、肿瘤细胞-血小板粘附、重组蛋白和色氨酸羟化酶1 （Tph1）敲除小鼠，研究了肝转移生态位中血小板与肿瘤细胞之间的串扰。结果：mCherry转移小生境标记系统显示PDAC患者肝转移小生境中存在活化血小板。血小板消耗降低小鼠肝转移瘤生长。在机制上，肿瘤细胞表达的EPHB1和血小板表达的Ephrin B1 （EFNB1）通过反向信号介导的AKT信号激活介导血小板接触依赖性活化，进而激活血小板释放的5-HT，进一步促进肿瘤生长。结论：我们揭示了PDAC肝转移生态位中血小板与肿瘤细胞之间的串扰。由EPHB1-EFNB1反向信号介导的肿瘤-血小板相互作用通过5-HT在肝脏中促进转移性PDAC的生长。通过靶向EPHB1-EFNB1轴干扰肿瘤-血小板相互作用可能是一种有希望的PDAC肝转移治疗干预措施。

{"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, Wei-Ting Qin, Li-Peng Hu, Tie-Zhu Shi, Jian Yu Yang, Qing Li, Hui-Zhen Nie, Jun Li, Xu Wang, Lei Zhu, De-Jun Liu, Yan-Li Zhang, Shu-Heng Jiang, Zhi-Gang Zhang, Xiao-Mei Yang, Dong-Xue Li, 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 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.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 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 (Ephb1), tumor cell-platelet adhesion, recombinant protein, and tryptophan hydroxylase 1 (Tph1)-knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 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.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 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.\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}

引用次数: 0

Vascular smooth muscle cell plasticity in the tumor microenvironment 血管平滑肌细胞在肿瘤微环境中的可塑性。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-12-08 DOI: 10.1002/cac2.12635

Caitlin F. Bell, Richard A. Baylis, Nicolas G. Lopez, Wei Feng Ma, Hua Gao, Fudi Wang, Sharika Bamezai, Changhao Fu, Yoko Kojima, Shaunak S. Adkar, Lingfeng Luo, Clint L. Miller, Nicholas J. Leeper

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 Acta2 and Myh11), increased proliferation and migration, and the upregulation of genes typically associated with other cell types, such as macrophages [1-3]. 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 [1-4]. 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.Two-colored Myh11 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+ lineage traced cells, indicating that they may have been misidentified using traditional histological approaches (Figure 1C). eGFP+ 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) [5].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+ 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

{"title":"Vascular smooth muscle cell plasticity in the tumor microenvironment","authors":"Caitlin F. Bell, Richard A. Baylis, Nicolas G. Lopez, Wei Feng Ma, Hua Gao, Fudi Wang, Sharika Bamezai, Changhao Fu, Yoko Kojima, Shaunak S. Adkar, Lingfeng Luo, Clint L. Miller, Nicholas J. Leeper","doi":"10.1002/cac2.12635","DOIUrl":"10.1002/cac2.12635","url":null,"abstract":"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 Acta2 and Myh11), increased proliferation and migration, and the upregulation of genes typically associated with other cell types, such as macrophages [1-3]. 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 [1-4]. 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.Two-colored Myh11 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+ lineage traced cells, indicating that they may have been misidentified using traditional histological approaches (Figure 1C). eGFP+ 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) [5].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+ 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}

引用次数: 0

SYNCRIP promotes cell cycle progression and lung tumorigenesis by modulating AURKB translation SYNCRIP通过调节AURKB翻译促进细胞周期进展和肺肿瘤发生。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-12-05 DOI: 10.1002/cac2.12634

Hyeon Ji Kim, Hye Guk Ryu, Mingyu Kang, Namgyu Lee, Hyo-Jin Kim, Dahye Lee, Chaeuk Chung, Sangjune Kim, Kyung-Ha Lee, Wanil Kim, Jin-Seok Byun, Kyong-Tai Kim, Do-Yeon Kim

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 [1]. 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 [2]. Although mechanisms that enhance AURKB activity, including binding to INCENP, autophosphorylation [3], and ubiquitination by TRAF6 [4], 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 [5], integrating various aspects of RNA metabolism with key cellular processes. Here, we aim to elucidate the mechanism of AURKB mRNA translation and investigate whether SYNCRIP regulates AURKB mRNA translation in lung cancer.To investigate the mechanisms underlying AURKB 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 AURKB 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 AURKB mRNA positioned between the coding sequences for Renilla (RLUC) and Firefly (FLUC) luciferases (Supplementary Figure S1C). This experiment confirmed that the AURKB 5’-UTR facilitates translation of a downstream cistron in a cap-independent manner (Figure 1B, Supplementary Figure S1D).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) [6]. 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

{"title":"SYNCRIP promotes cell cycle progression and lung tumorigenesis by modulating AURKB translation","authors":"Hyeon Ji Kim, Hye Guk Ryu, Mingyu Kang, Namgyu Lee, Hyo-Jin Kim, Dahye Lee, Chaeuk Chung, Sangjune Kim, Kyung-Ha Lee, Wanil Kim, Jin-Seok Byun, Kyong-Tai Kim, Do-Yeon Kim","doi":"10.1002/cac2.12634","DOIUrl":"10.1002/cac2.12634","url":null,"abstract":"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 [1]. 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 [2]. Although mechanisms that enhance AURKB activity, including binding to INCENP, autophosphorylation [3], and ubiquitination by TRAF6 [4], 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 [5], integrating various aspects of RNA metabolism with key cellular processes. Here, we aim to elucidate the mechanism of AURKB mRNA translation and investigate whether SYNCRIP regulates AURKB mRNA translation in lung cancer.To investigate the mechanisms underlying AURKB 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 AURKB 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 AURKB mRNA positioned between the coding sequences for Renilla (RLUC) and Firefly (FLUC) luciferases (Supplementary Figure S1C). This experiment confirmed that the AURKB 5’-UTR facilitates translation of a downstream cistron in a cap-independent manner (Figure 1B, Supplementary Figure S1D).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) [6]. 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}

引用次数: 0

Nicotinamide N-methyltransferase negatively regulates metastasis-promoting property of cancer-associated fibroblasts in lung adenocarcinoma 烟酰胺n -甲基转移酶负调控肺腺癌中癌相关成纤维细胞的转移促进特性。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-12-02 DOI: 10.1002/cac2.12633

Peiyu Wang, Guangxi Wang, Haoran Li, Yuyao Yuan, Haiming Chen, Shaodong Wang, Zewen Sun, Fanjie Meng, Yun Li, Fan Yang, Jun Wang, Kezhong Chen, Mantang Qiu

<div> <section> <h3> Background</h3> 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. </section> <section> <h3> Methods</h3> 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. </section> <section> <h3> Results</h3> 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 NNMT 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. </section> <section> <h3> Conclusions</h3> This study provides novel insights into the metabolic and epigenetic regulatory

背景：肺腺癌（LUAD）根治后复发和转移仍然是一个重大挑战。LUAD复发和转移的机制尚不清楚，细胞代谢失调可能起重要作用。本研究探讨了烟酰胺n -甲基转移酶（NNMT）在LUAD中的代谢和表观遗传调控。方法：采用非靶向代谢组学分析检测代谢异常。使用单细胞RNA测序（RNA-seq）数据库和多重免疫荧光分析来确定NNMT在肿瘤微环境中的位置。在体外和体内研究了NNMT的生物学功能，通过RNA-seq和染色质免疫沉淀- pcr提供了潜在机制的见解。最后，对原发肿瘤的单细胞RNA-seq数据和免疫组织化学进行分析，以验证主要发现。结果：非靶向代谢组学分析揭示了氨基酸、有机酸、脂质和烟酰胺途径的代谢异常，这些代谢异常与非小细胞肺癌的转移有关。NNMT是烟酰胺代谢的关键酶，我们发现NNMT基因的整体组织mRNA水平与LUAD转移呈负相关。NNMT被证明主要表达于LUAD间质区域内的癌症相关成纤维细胞（CAFs）中，而间质NNMT的低表达被确定为LUAD根治性切除术后无病生存率差的预测因子。LUAD中CAFs的分离和原代培养实现了体外和体内实验，证实了NNMT负调控LUAD中CAFs促进转移的特性。从机制上讲，NNMT的下调通过降低蛋氨酸循环的活性导致细胞内甲基的增加，导致H3K4me3甲基化升高。这种改变触发了cas中参与细胞外基质重塑的基因上调，包括编码胶原蛋白、整合素、层粘连蛋白和基质金属蛋白酶的基因，从而促进了癌细胞的侵袭和转移。对原发性LUAD组织的单细胞RNA-seq数据和免疫组织化学分析证实了NNMT在cas中对这些基因的负调控。结论：本研究为NNMT在CAFs中的代谢和表观遗传调控功能提供了新的见解，扩展了目前对LUAD转移调控的理解，并为未来的研究和治疗开发提供了潜在的途径。

{"title":"Nicotinamide N-methyltransferase negatively regulates metastasis-promoting property of cancer-associated fibroblasts in lung adenocarcinoma","authors":"Peiyu Wang, Guangxi Wang, Haoran Li, Yuyao Yuan, Haiming Chen, Shaodong Wang, Zewen Sun, Fanjie Meng, Yun Li, Fan Yang, Jun Wang, Kezhong Chen, Mantang Qiu","doi":"10.1002/cac2.12633","DOIUrl":"10.1002/cac2.12633","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 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.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 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.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 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 NNMT 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.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 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}

引用次数: 0

Advances in cervical cancer: current insights and future directions 宫颈癌的进展：当前的见解和未来的方向。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-11-29 DOI: 10.1002/cac2.12629

Miaochun Xu, Canhui Cao, Peng Wu, Xiaoyuan Huang, Ding Ma

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.

根据世界卫生组织消除宫颈癌的战略，在治疗这种恶性肿瘤方面取得了重大进展。宫颈癌主要由人乳头瘤病毒（HPV）感染引起，由于其病因明确，因此被认为是可预防和可控的。精确筛查技术的进步，如DNA甲基化分诊、HPV整合检测、液体活检和人工智能辅助诊断，增强了传统的筛查方法，如HPV核酸检测和细胞学。旨在根除HPV和逆转癌前病变的治疗策略已被完善为疾病预防的关键措施。围绕早期宫颈癌手术的争议围绕着在不影响肿瘤预后的情况下确定微创和保守手术的最佳候选者。最近的临床试验为晚期宫颈癌的全身治疗的发展取得了可喜的结果。免疫疗法，如免疫检查点抑制剂（ICIs）、抗体-药物偶联物（adc）和靶向治疗已经证明了显著的有效性，标志着宫颈癌治疗的实质性进展。各种联合治疗已经得到验证，正在进行的试验旨在通过开发新药和优化联合治疗方案来提高疗效。根除子宫颈癌作为第一种被消灭的恶性肿瘤的前景现在是可以实现的。在这篇综述中，我们全面概述了最新的科学见解，重点介绍了宫颈癌各阶段疾病的精确管理，并探讨了宫颈癌未来的研究方向。

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引用次数: 0

PTPN9 regulates HER3 phosphorylation during trastuzumab treatment and loss of PTPN9 is a potential biomarker for trastuzumab resistance in HER2 positive breast cancer PTPN9 在曲妥珠单抗治疗过程中调节 HER3 磷酸化，而 PTPN9 的缺失是 HER2 阳性乳腺癌患者对曲妥珠单抗耐药的潜在生物标志物。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-11-24 DOI: 10.1002/cac2.12632

Abul Azad, Maryam Arshad, Daniele Generali, Katharina Feldinger, Merel Gijsen, Carla Strina, Mariarosa Cappelletti, Daniele Andreis, Russell Leek, Syed Haider, Pirkko-Liisa Kellokumpu-Lehtinen, Ioannis Roxanis, Adrian Llewellyn Harris, Abeer Mahmoud Shaaban, Heikki Joensuu, Anthony Kong

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 [1]. 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 [2], 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.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 [3, 4] (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 [1, 5]. 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).Next, we

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引用次数: 0

Ex vivo STAT3 phosphorylation in circulating immune cells: a novel biomarker for early cancer diagnosis and response to anti-PD-1 therapy 循环免疫细胞中的体外 STAT3 磷酸化：早期癌症诊断和抗 PD-1 治疗反应的新型生物标记物。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-11-20 DOI: 10.1002/cac2.12631

Sung-Woo Lee, Young Ju Kim, Saei Jeong, Kyung Na Rho, Jeong Eun Noh, Hee-Ok Kim, Hyun-Ju Cho, Yoo Duk Choi, Deok Hwan Yang, Eu Chang Hwang, Woo Kyun Bae, Sook Jung Yun, Ju Sik Yun, Cheol-Kyu Park, In-Jae Oh, Jae-Ho Cho

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 [1]. 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 [2, 3], we aimed to investigate basal STAT3 activation in blood by developing a methodology to assess ex vivo phosphorylation of STAT3 (pSTAT3ex vivo) in circulating immune cells.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 pSTAT3ex vivo-positive cells compared to healthy controls (Figure 1B and Supplementary Table S1). Prolonged handling and extended experimental steps significantly decreased pSTAT3ex vivo expression (Supplementary Figure S1), underscoring the importance of our novel approach in controlling the time between blood collection and the experiment.We next investigated the cell types within PBMCs that express pSTAT3ex vivo. CD4+ T cells exhibited the highest pSTAT3ex vivo expression, followed by CD8+ T cells, whereas monocytes, B cells, and natural killer (NK) cells showed minimal pSTAT3ex vivo expression (Figure 1C). Within both CD4+ and CD8+ T cells, pSTAT3ex vivo expression was highest in the least differentiated CD27+ CD45RA+ naïve subset (Figure 1C) [4]. A similar pattern was observed across multiple other cancer types (Figure 1D and Supplementary Figure S2).Focusing on CD4+ naïve T cells, pSTAT3ex vivo 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 pSTAT3ex vivo expression in NSCLC patients (Supplementary Figure S3), while surgical removal of the tumor decreased pSTAT3ex vivo expression (Figure 1G), supporting a direct association between pSTAT3ex vivo and tumor burden. These findings underscore the potential of pSTAT3ex vivo as a blood-

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引用次数: 0