IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-11-14 DOI: 10.1016/j.neo.2024.101083

Lisa Staffeldt , Hanna Maar , Julia Beimdiek , Samuel Chambers , Kristoffer Riecken , Mark von Itzstein , Falk F.R. Buettner , Arun Everest-Dass , Tobias Lange

The commonly altered glycosylation of tumor cells is a hallmark of tumor progression and metastasis formation. One prominent example is the interaction of sialylated glycans at the tumor cell surface with endothelial (E)-selectin as an early event of an adhesion cascade that enables extravasation of circulating tumor cells (CTCs) into distant tissues. In a previous study, we identified GCNT3 (mucin-type core2/ core4 β1,6-N-acetylglucosaminyltransferase) highly over-expressed in gastrointestinal adenocarcinoma cells that facilitate the canonical E-selectin ligands sialyl-Lewis A and X (sLeA/X) for E-selectin binding and endothelial adhesion. Here we show that shRNA-mediated, stable depletion of GCNT3 reduced sLeA (tumor marker CA19-9) presentation on two out of three tested human gastrointestinal adenocarcinoma cell lines, concurrently showing reduced static E-selectin binding. Significant effects of GCNT3 depletion on dynamic, shear-resistant tumor cell adhesion on immobilized E-selectin as well as endothelial cells were only partially and inconsistently observable as were effects on tumor cell proliferation (2D) or 3D colony formation. Nevertheless, tumor cell migration was consistently reduced upon GCNT3 depletion in all tested cell lines. Detailed glycome analyses revealed that GCNT3 depletion caused cell line-specific alterations in N- and O-glycans as well as glycosphingolipids, collectively mainly associating with decreased Core-2 structures resulting in varied abundance of sialylation and Lewis antigen with consistent phenotypic changes. Distinctive N- and O-glycosylation features were found to be inherent to specific cell types. These findings suggest GCNT3 products as possible carriers of sLeA and static E-selectin binding sites as well as common pro-migratory glycans in human gastrointestinal cancer.

肿瘤细胞常见的糖基化改变是肿瘤进展和转移形成的标志。一个突出的例子是肿瘤细胞表面的糖基化聚糖与内皮（E）-选择素的相互作用，这是粘附级联的早期事件，可使循环肿瘤细胞（CTC）外渗至远处组织。在之前的一项研究中，我们发现胃肠道腺癌细胞中高度过表达的 GCNT3（粘蛋白型核2/核4 β1,6-N-乙酰葡糖胺基转移酶）能促进 E 选择素配体 sialyl-Lewis A 和 X（sLeA/X）与 E 选择素结合和内皮粘附。在这里，我们发现 shRNA 介导的 GCNT3 稳定性缺失减少了 sLeA（肿瘤标志物 CA19-9）在三种受测人类胃肠道腺癌细胞系中两种细胞系上的呈现，同时显示出静态 E-选择素结合的减少。GCNT3 基因耗竭对固定 E 选择素上的动态、抗剪切肿瘤细胞粘附以及内皮细胞的显著影响只有部分且不一致的观察结果，对肿瘤细胞增殖（2D）或三维集落形成的影响也是如此。然而，在所有测试的细胞系中，GCNT3 消耗后肿瘤细胞的迁移率持续降低。详细的糖分子结构分析表明，GCNT3 缺失会引起细胞系特异性的 N-和 O-聚糖以及糖磷脂的改变，这些改变主要与核心-2 结构的减少有关，从而导致硅烷基化和路易斯抗原的丰度不同，并产生一致的表型变化。研究发现，特定细胞类型固有独特的 N-和 O-糖基化特征。这些发现表明，GCNT3 产品可能是 sLeA 和静态 E 选择素结合位点的载体，也可能是人类胃肠癌中常见的促迁移聚糖。

{"title":"Depletion of β1,6-N-acetylglucosaminyltransferase reduces E-selectin binding capacity and migratory potential of human gastrointestinal adenocarcinoma cells","authors":"Lisa Staffeldt , Hanna Maar , Julia Beimdiek , Samuel Chambers , Kristoffer Riecken , Mark von Itzstein , Falk F.R. Buettner , Arun Everest-Dass , Tobias Lange","doi":"10.1016/j.neo.2024.101083","DOIUrl":"10.1016/j.neo.2024.101083","url":null,"abstract":"<div><div>The commonly altered glycosylation of tumor cells is a hallmark of tumor progression and metastasis formation. One prominent example is the interaction of sialylated glycans at the tumor cell surface with endothelial (E)-selectin as an early event of an adhesion cascade that enables extravasation of circulating tumor cells (CTCs) into distant tissues. In a previous study, we identified GCNT3 (mucin-type core2/ core4 β1,6-<em>N</em>-acetylglucosaminyltransferase) highly over-expressed in gastrointestinal adenocarcinoma cells that facilitate the canonical E-selectin ligands sialyl-Lewis A and X (sLeA/X) for E-selectin binding and endothelial adhesion. Here we show that shRNA-mediated, stable depletion of GCNT3 reduced sLeA (tumor marker CA19-9) presentation on two out of three tested human gastrointestinal adenocarcinoma cell lines, concurrently showing reduced static E-selectin binding. Significant effects of GCNT3 depletion on dynamic, shear-resistant tumor cell adhesion on immobilized E-selectin as well as endothelial cells were only partially and inconsistently observable as were effects on tumor cell proliferation (2D) or 3D colony formation. Nevertheless, tumor cell migration was consistently reduced upon GCNT3 depletion in all tested cell lines. Detailed glycome analyses revealed that GCNT3 depletion caused cell line-specific alterations in <em>N</em>- and <em>O</em>-glycans as well as glycosphingolipids, collectively mainly associating with decreased Core-2 structures resulting in varied abundance of sialylation and Lewis antigen with consistent phenotypic changes. Distinctive <em>N</em>- and <em>O</em>-glycosylation features were found to be inherent to specific cell types. These findings suggest GCNT3 products as possible carriers of sLeA and static E-selectin binding sites as well as common pro-migratory glycans in human gastrointestinal cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101083"},"PeriodicalIF":4.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel regimen for pancreatic ductal adenocarcinoma targeting MEK, BCL-xL, and EGFR 针对MEK、BCL-xL和表皮生长因子受体的胰腺导管腺癌新疗法。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-11-14 DOI: 10.1016/j.neo.2024.101070

Song Han , Gerik W. Tushoski-Alemán , Peiyi Zhang , Guangrong Zheng , Daohong Zhou , Zhiguang Huo , Jonathan Licht , Thomas J. George , Carmen Allegra , Jose G. Trevino , Steven J. Hughes

Oncogenic KRAS signaling plays a critical role in pancreatic ductal adenocarcinoma (PDAC) biology. Recent studies indicate that the combination of MEK and BCL-xL inhibition is synthetically lethal and holds promise for some types of solid cancers, however, patient response was poorly observed in PDAC predominantly due to amplified EGFR signaling. Here, we leverage the advantage of the combinational treatment strategy and designed a triplet regimen targeting the comprehensive RAS activation networks through simultaneously blocking MEK/BCL-xL/EGFR. The cytotoxicity of trametinib (MEK inhibitor), DT2216 (BCL-xL degrader) and afatinib (pan-EGFR inhibitor) and their combination was tested in patient-derived, primary PDAC cells using a live cell imaging system. Patient-derived xenograft (PDX) model was employed for the evaluation of the therapeutic efficacy and safety of the combinational regimen. Targeted pathway cascades activities were analyzed using multiplex phosphor-immune assays. In vitro comparisons showed the addition of afatinib as a third agent was statistically superior compared to a doublet of trametinib+DT2216 in suppressing cell growth and inducing cell death in all cell lines tested. This triplet similarly demonstrated significant superiority over the doublet of MEK/BCL-xL inhibition in the in vivo murine model. The triplet regimen was well tolerated in vivo. Overall tumor growth rates were significantly reduced in doublet treatment compared to controls, and further reduced in the triplet treatment group. Pathway analysis revealed the addition of afatinib in triplet regimen further inhibited PI3K/AKT effectors of p90RSK, p70S6K, and GSK3α/β along with a secondary pathway of P38 MAPK. Our study identifies an important contribution of EGFR inhibition to elevate the response of PDAC, supporting a clinical assessment of this triplet combination in patients.

致癌 KRAS 信号在胰腺导管腺癌（PDAC）生物学中起着关键作用。最近的研究表明，MEK 和 BCL-xL 联合抑制具有合成杀伤力，有望用于某些类型的实体瘤，但主要由于表皮生长因子受体（EGFR）信号的扩增，在 PDAC 中观察到的患者反应不佳。在这里，我们利用联合治疗策略的优势，设计了一种三联疗法，通过同时阻断MEK/BCL-xL/EGFR，靶向全面的RAS激活网络。利用活细胞成像系统在患者来源的原发性PDAC细胞中测试了曲美替尼（MEK抑制剂）、DT2216（BCL-xL降解剂）和阿法替尼（泛EGFR抑制剂）及其组合的细胞毒性。患者衍生异种移植（PDX）模型用于评估组合疗法的疗效和安全性。使用多重荧光免疫测定分析了靶向通路级联的活性。体外比较显示，与曲美替尼+DT2216双联疗法相比，添加阿法替尼作为第三种药物在抑制细胞生长和诱导细胞死亡方面具有统计学优势。同样，在体内小鼠模型中，该三联疗法的MEK/BCL-xL抑制效果也明显优于双联疗法。三联疗法在体内耐受性良好。与对照组相比，双联治疗组的总体肿瘤生长率明显降低，三联治疗组的肿瘤生长率进一步降低。通路分析表明，在三联疗法中加入阿法替尼进一步抑制了PI3K/AKT效应因子p90RSK、p70S6K和GSK3α/β以及次级通路P38 MAPK。我们的研究确定了表皮生长因子受体抑制对提高 PDAC 反应的重要贡献，支持对患者进行这种三联疗法的临床评估。

{"title":"A novel regimen for pancreatic ductal adenocarcinoma targeting MEK, BCL-xL, and EGFR","authors":"Song Han , Gerik W. Tushoski-Alemán , Peiyi Zhang , Guangrong Zheng , Daohong Zhou , Zhiguang Huo , Jonathan Licht , Thomas J. George , Carmen Allegra , Jose G. Trevino , Steven J. Hughes","doi":"10.1016/j.neo.2024.101070","DOIUrl":"10.1016/j.neo.2024.101070","url":null,"abstract":"<div><div>Oncogenic KRAS signaling plays a critical role in pancreatic ductal adenocarcinoma (PDAC) biology. Recent studies indicate that the combination of MEK and BCL-xL inhibition is synthetically lethal and holds promise for some types of solid cancers, however, patient response was poorly observed in PDAC predominantly due to amplified EGFR signaling. Here, we leverage the advantage of the combinational treatment strategy and designed a triplet regimen targeting the comprehensive RAS activation networks through simultaneously blocking MEK/BCL-xL/EGFR. The cytotoxicity of trametinib (MEK inhibitor), DT2216 (BCL-xL degrader) and afatinib (pan-EGFR inhibitor) and their combination was tested in patient-derived, primary PDAC cells using a live cell imaging system. Patient-derived xenograft (PDX) model was employed for the evaluation of the therapeutic efficacy and safety of the combinational regimen. Targeted pathway cascades activities were analyzed using multiplex phosphor-immune assays. <em>In vitro</em> comparisons showed the addition of afatinib as a third agent was statistically superior compared to a doublet of trametinib+DT2216 in suppressing cell growth and inducing cell death in all cell lines tested. This triplet similarly demonstrated significant superiority over the doublet of MEK/BCL-xL inhibition in the <em>in vivo</em> murine model. The triplet regimen was well tolerated <em>in viv</em>o. Overall tumor growth rates were significantly reduced in doublet treatment compared to controls, and further reduced in the triplet treatment group. Pathway analysis revealed the addition of afatinib in triplet regimen further inhibited PI3K/AKT effectors of p90RSK, p70S6K, and GSK3α/β along with a secondary pathway of P38 MAPK. Our study identifies an important contribution of EGFR inhibition to elevate the response of PDAC, supporting a clinical assessment of this triplet combination in patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101070"},"PeriodicalIF":4.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel regulatory axis of MSI2-AGO2/miR-30a-3p-CGRRF1 drives cancer chemoresistance by upregulating the KRAS/ERK pathway MSI2-AGO2/miR-30a-3p-CGRRF1的新型调控轴通过上调KRAS/ERK通路驱动癌症化疗抗性。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-11-09 DOI: 10.1016/j.neo.2024.101082

Runhui Lu , Yafan Zhang , Ran Chen , Lian Li , Caihu Huang , Zihan Zhou , Yingting Cao , Hongyan Li , Junya Li , Yixin Zhang , Yanli Wang , Jian Huang , Xian Zhao , Jing Feng , Jianxiu Yu , Chunling Du

The KRAS/ERK pathway is crucial in cancer progression and chemotherapy resistance, yet its upstream regulatory mechanism remains elusive. We identified MSI2 as a new promoter of chemotherapy resistance in cancers. MSI2 directly binds to a specific class of mature miRNAs by recognizing the 'UAG' motif and interacts with the essential effector AGO2, highlighting MSI2 as a novel regulatory factor within the miRNA pathway. Specifically, MSI2 recruits UAG-miRNA miR-30a-3p to facilitate its loading onto AGO2, efficiently inhibiting the expression of CGRRF1. Further analysis reveals that CGRRF1 functions as a new ubiquitin E3 ligase for KRAS, mediating the ubiquitination and proteasome degradation of KRAS. Consequently, a novel regulatory axis involving MSI2-AGO2/miR-30a-3p-CGRRF1 positively regulates the KRAS/ERK pathway. Remarkably, platinum-based chemotherapy drugs significantly enhance the levels of phosphorylated ERK1/2 (p-ERK1/2) in cancer cells, and the EGFR inhibitor Gefitinib also increases p-ERK1/2 levels in Gefitinib-resistant cancer cells. Combining small-molecule inhibitors targeting MSI2, such as Ro 08-2750, efficiently alleviated chemoresistance in tumor cells exposed to Platinum and Gefitinib. These findings suggest that MSI2 could be a novel therapeutic target for developing strategies to counteract cancer resistance to treatment.

KRAS/ERK通路在癌症进展和化疗耐药性中至关重要，但其上游调控机制仍然难以捉摸。我们发现 MSI2 是癌症化疗耐药性的新启动子。MSI2通过识别 "UAG "基序直接与一类特定的成熟miRNA结合，并与重要的效应因子AGO2相互作用，从而凸显了MSI2是miRNA通路中的一种新型调控因子。具体地说，MSI2 会吸引 UAG-miRNA miR-30a-3p 加载到 AGO2 上，从而有效抑制 CGRRF1 的表达。进一步分析表明，CGRRF1 可作为 KRAS 新的泛素 E3 连接酶，介导 KRAS 的泛素化和蛋白酶体降解。因此，一个涉及 MSI2-AGO2/miR-30a-3p-CGRRF1 的新型调控轴正调控着 KRAS/ERK 通路。值得注意的是，铂类化疗药物会显著提高癌细胞中磷酸化 ERK1/2（p-ERK1/2）的水平，而表皮生长因子受体抑制剂吉非替尼（Gefitinib）也会提高吉非替尼耐药癌细胞中 p-ERK1/2 的水平。联合使用靶向MSI2的小分子抑制剂（如Ro 08-2750），可有效缓解暴露于铂类和吉非替尼的肿瘤细胞的化疗耐药性。这些研究结果表明，MSI2可能是一种新型治疗靶点，可用于开发抗击癌症耐药性的策略。

{"title":"A novel regulatory axis of MSI2-AGO2/miR-30a-3p-CGRRF1 drives cancer chemoresistance by upregulating the KRAS/ERK pathway","authors":"Runhui Lu , Yafan Zhang , Ran Chen , Lian Li , Caihu Huang , Zihan Zhou , Yingting Cao , Hongyan Li , Junya Li , Yixin Zhang , Yanli Wang , Jian Huang , Xian Zhao , Jing Feng , Jianxiu Yu , Chunling Du","doi":"10.1016/j.neo.2024.101082","DOIUrl":"10.1016/j.neo.2024.101082","url":null,"abstract":"<div><div>The KRAS/ERK pathway is crucial in cancer progression and chemotherapy resistance, yet its upstream regulatory mechanism remains elusive. We identified MSI2 as a new promoter of chemotherapy resistance in cancers. MSI2 directly binds to a specific class of mature miRNAs by recognizing the 'UAG' motif and interacts with the essential effector AGO2, highlighting MSI2 as a novel regulatory factor within the miRNA pathway. Specifically, MSI2 recruits UAG-miRNA miR-30a-3p to facilitate its loading onto AGO2, efficiently inhibiting the expression of CGRRF1. Further analysis reveals that CGRRF1 functions as a new ubiquitin E3 ligase for KRAS, mediating the ubiquitination and proteasome degradation of KRAS. Consequently, a novel regulatory axis involving MSI2-AGO2/miR-30a-3p-CGRRF1 positively regulates the KRAS/ERK pathway. Remarkably, platinum-based chemotherapy drugs significantly enhance the levels of phosphorylated ERK1/2 (p-ERK1/2) in cancer cells, and the EGFR inhibitor Gefitinib also increases p-ERK1/2 levels in Gefitinib-resistant cancer cells. Combining small-molecule inhibitors targeting MSI2, such as Ro 08-2750, efficiently alleviated chemoresistance in tumor cells exposed to Platinum and Gefitinib. These findings suggest that MSI2 could be a novel therapeutic target for developing strategies to counteract cancer resistance to treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101082"},"PeriodicalIF":4.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aurora kinase B is required for growth and expansion of medulloblastoma cells in the tissue context 髓母细胞瘤细胞在组织环境中的生长和扩增需要极光激酶 B。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-11-08 DOI: 10.1016/j.neo.2024.101078

Alexandre Gries , Karthiga Santhana Kumar , Fabien Kuttler , Özgün Özalp , Veronica Akle , Hanqing Zhang , Michael A. Grotzer , Stephan C.F. Neuhauss , Amin Allalou , Martin Baumgartner

The impact of the tissue context on tumor growth and drug response in medulloblastoma (MB) is poorly understood. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with ex vivo organotypic cerebellum slice co-culture (OCSC), which allowed the assessment of tumor cell behavior in the tissue context.

To identify druggable kinase pathways involved in invasion, we screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) Barasertib (AZD1152-HQPA) and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, and Grp3 MB. Importantly, AURKBi are tumor suppressive in the tissue context, also in MB tumor cells that are in vitro resistant to the same treatment. We confirmed the requirement of AURKB for tumor growth and expansion in the tissue context through genetic suppression of AURKB by siRNA. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor Dasatinib acts synergistically to repress tumor growth and expansion in the highly invasive MB cell model ONS-76, but not in Grp3 MB cells. We demonstrate that tumor growth in the tissue context is suppressed by pharmacological inhibition of AURKB, comparable to the growth reduction observed after X-ray irradiation, which was used as the positive control. Finally, we show that exposure to µM concentrations of Barasertib does not cause developmental toxicity in fish larvae.

In conclusion, we demonstrate that AURKB is essential for MB tumor growth and expansion in the tissue context and the inhibition of AURKB is equally efficient as irradiation in repressing tumor cell growth. In patients younger than three years, pharmacological targeting of AURKB may thus constitute a novel means to overcome radiotherapy limitations.

人们对髓母细胞瘤（MB）的组织环境对肿瘤生长和药物反应的影响知之甚少。为了深入了解接受治疗的髓母细胞瘤肿瘤细胞的生长和扩散行为，我们将三维细胞培养筛选与体外有机小脑切片共培养（OCSC）相结合，从而评估了肿瘤细胞在组织环境中的行为。为了确定参与侵袭的可药用激酶通路，我们筛选了274种激酶抑制剂，并确定极光激酶B（AURKB）是MB潜在的抗侵袭药物靶点。我们在小脑切片培养模型中验证了AURKB抑制剂（AURKBi）Barasertib（AZD1152-HQPA）和结构不相关的化合物GSK-1070916对SHH和Grp3 MB的抑瘤活性。重要的是，AURKBi 在组织环境中具有抑制肿瘤的作用，在体外对相同治疗具有抗药性的 MB 肿瘤细胞中也是如此。我们通过 siRNA 基因抑制 AURKB，证实了 AURKB 在组织环境中对肿瘤生长和扩张的要求。我们发现，在高侵袭性 MB 细胞模型 ONS-76 中，AURKBi 与 SRC/BCR-ABL 抑制剂达沙替尼联用可协同抑制肿瘤的生长和扩张，但在 Grp3 MB 细胞中则无效。我们证明，药理抑制 AURKB 可抑制组织中的肿瘤生长，与作为阳性对照的 X 射线照射后观察到的肿瘤生长减少效果相当。最后，我们还发现，暴露于 µM 浓度的巴拉塞替不会对鱼类幼体造成发育毒性。总之，我们证明了 AURKB 对 MB 肿瘤在组织环境中的生长和扩张至关重要，抑制 AURKB 与照射抑制肿瘤细胞生长的效果相同。因此，对于三岁以下的患者，以 AURKB 为药物靶点可能是克服放疗局限性的一种新方法。

{"title":"Aurora kinase B is required for growth and expansion of medulloblastoma cells in the tissue context","authors":"Alexandre Gries , Karthiga Santhana Kumar , Fabien Kuttler , Özgün Özalp , Veronica Akle , Hanqing Zhang , Michael A. Grotzer , Stephan C.F. Neuhauss , Amin Allalou , Martin Baumgartner","doi":"10.1016/j.neo.2024.101078","DOIUrl":"10.1016/j.neo.2024.101078","url":null,"abstract":"<div><div>The impact of the tissue context on tumor growth and drug response in medulloblastoma (MB) is poorly understood. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with <em>ex vivo</em> organotypic cerebellum slice co-culture (OCSC), which allowed the assessment of tumor cell behavior in the tissue context.</div><div>To identify druggable kinase pathways involved in invasion, we screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) Barasertib (AZD1152-HQPA) and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, and Grp3 MB. Importantly, AURKBi are tumor suppressive in the tissue context, also in MB tumor cells that are <em>in vitro</em> resistant to the same treatment. We confirmed the requirement of AURKB for tumor growth and expansion in the tissue context through genetic suppression of AURKB by siRNA. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor Dasatinib acts synergistically to repress tumor growth and expansion in the highly invasive MB cell model ONS-76, but not in Grp3 MB cells. We demonstrate that tumor growth in the tissue context is suppressed by pharmacological inhibition of AURKB, comparable to the growth reduction observed after X-ray irradiation, which was used as the positive control. Finally, we show that exposure to µM concentrations of Barasertib does not cause developmental toxicity in fish larvae.</div><div>In conclusion, we demonstrate that AURKB is essential for MB tumor growth and expansion in the tissue context and the inhibition of AURKB is equally efficient as irradiation in repressing tumor cell growth. In patients younger than three years, pharmacological targeting of AURKB may thus constitute a novel means to overcome radiotherapy limitations.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101078"},"PeriodicalIF":4.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cancer incidence and mortality among patients with new-onset atrial fibrillation: A population-based matched cohort study 新发心房颤动患者的癌症发病率和死亡率：基于人群的匹配队列研究

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-11-08 DOI: 10.1016/j.neo.2024.101080

Nadine Zakkak , Matthew Barclay , Arturo Gonzalez-Izquierdo , Amand Floriaan Schmidt , Gregory Y.H. Lip , Georgios Lyratzopoulos , Rui Providencia

Background

Understanding the risk of cancer after the diagnosis of another condition can present opportunities for earlier diagnosis. We examined the risk of cancer diagnosis conditional on prior diagnosis of atrial fibrillation (AF).

Methods

Linked electronic health records were used to identify patients aged ≥18 with new-onset AF and age-sex-matched controls. Cumulative incidence of and mortality from cancer (overall and cancer-site specific) within three months, three months to five years and beyond five years from diagnosis of AF were examined. Findings were further validated using Mendelian randomisation (MR).

Results

The cohort included 117,173 patients with new-onset AF and 117,173 matched controls (median age 78). In the first three months, 2.2% of AF patients were diagnosed with cancer vs. 0.47% in controls (relative risk: 4.7 [95%CI 4.2-5.4] in men and 4.4 [95%CI 3.8-5.0] in women). Nearly 80% of cancers related to thoracic or abdominal organs. Differences in cumulative incidence were only evident in women between three months and five years (subdistribution hazard ratio=1.1 [95%CI 1.01-1.12]) and absent in all patients beyond five years. MR analysis did not support the presence of a causal association between AF and major cancer subtypes.

Conclusion

There is a large short-term increase in cancer incidence and mortality following new-onset AF. The findings may reflect incidental identification of AF or paraneoplastic manifestation. New-onset AF confers high short-term risk of cancer diagnosis, at levels comparable with symptomatic risk threshold mandating urgent assessment for suspected cancer.

背景：了解确诊其他疾病后的癌症风险可为早期诊断提供机会。我们研究了之前诊断出心房颤动（房颤）的癌症诊断风险：方法：使用关联的电子健康记录来识别年龄≥18 岁的新发房颤患者和年龄性别匹配的对照组。研究人员对心房颤动确诊后三个月内、三个月至五年内以及五年后的癌症累积发病率和死亡率（总体和癌症部位特异性）进行了检测。结果：队列包括 117173 名新发房颤患者和 117173 名匹配对照者（中位年龄为 78 岁）。在最初的三个月中，2.2%的房颤患者被诊断出患有癌症，而对照组的这一比例为 0.47%（相对风险：男性为 4.7 [95%CI 4.2-5.4]，女性为 4.4 [95%CI 3.8-5.0]）。近 80% 的癌症与胸部或腹部器官有关。累积发病率的差异仅在三个月至五年之间的女性中明显（亚分布危险比=1.1 [95%CI 1.01-1.12]），五年以上的所有患者中均无差异。MR分析不支持房颤与主要癌症亚型之间存在因果关系：结论：新发房颤后，癌症发病率和死亡率会在短期内大幅上升。结论：新发房颤后癌症发病率和死亡率在短期内大幅上升，这些发现可能反映了偶然发现的房颤或副肿瘤表现。新发房颤具有较高的短期癌症诊断风险，其水平与症状风险阈值相当，因此必须对疑似癌症进行紧急评估。

{"title":"Cancer incidence and mortality among patients with new-onset atrial fibrillation: A population-based matched cohort study","authors":"Nadine Zakkak , Matthew Barclay , Arturo Gonzalez-Izquierdo , Amand Floriaan Schmidt , Gregory Y.H. Lip , Georgios Lyratzopoulos , Rui Providencia","doi":"10.1016/j.neo.2024.101080","DOIUrl":"10.1016/j.neo.2024.101080","url":null,"abstract":"<div><h3>Background</h3><div>Understanding the risk of cancer after the diagnosis of another condition can present opportunities for earlier diagnosis. We examined the risk of cancer diagnosis conditional on prior diagnosis of atrial fibrillation (AF).</div></div><div><h3>Methods</h3><div>Linked electronic health records were used to identify patients aged ≥18 with new-onset AF and age-sex-matched controls. Cumulative incidence of and mortality from cancer (overall and cancer-site specific) within three months, three months to five years and beyond five years from diagnosis of AF were examined. Findings were further validated using Mendelian randomisation (MR).</div></div><div><h3>Results</h3><div>The cohort included 117,173 patients with new-onset AF and 117,173 matched controls (median age 78). In the first three months, 2.2% of AF patients were diagnosed with cancer vs. 0.47% in controls (relative risk: 4.7 [95%CI 4.2-5.4] in men and 4.4 [95%CI 3.8-5.0] in women). Nearly 80% of cancers related to thoracic or abdominal organs. Differences in cumulative incidence were only evident in women between three months and five years (subdistribution hazard ratio=1.1 [95%CI 1.01-1.12]) and absent in all patients beyond five years. MR analysis did not support the presence of a causal association between AF and major cancer subtypes.</div></div><div><h3>Conclusion</h3><div>There is a large short-term increase in cancer incidence and mortality following new-onset AF. The findings may reflect incidental identification of AF or paraneoplastic manifestation. New-onset AF confers high short-term risk of cancer diagnosis, at levels comparable with symptomatic risk threshold mandating urgent assessment for suspected cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101080"},"PeriodicalIF":4.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities 糖酵解在肿瘤发生中的作用：从生物学方面到治疗机会。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-10-30 DOI: 10.1016/j.neo.2024.101076

Marco Cordani , Federica Michetti , Ali Zarrabi , Atefeh Zarepour , Cristiano Rumio , Raffaele Strippoli , Fabrizio Marcucci

Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as “moonlighting” functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.

糖酵解代谢产生能量和中间产物，用于生产生物质。与正常组织相比，肿瘤相关的糖酵解在肿瘤细胞自主或非自主刺激下上调。这种上调的后果有两个方面。首先，糖酵解的代谢作用超过氧化代谢作用。其次，糖酵解途径的过表达成分（即酶或代谢物）获得了与其代谢作用无关的新功能，这些功能被称为 "月光 "功能。这些功能包括诱导突变和其他肿瘤诱发事件、对癌症干细胞的影响、诱导增加肿瘤蛋白的表达和/或活性、表观遗传和转录修饰、绕过衰老和诱导增殖、促进 DNA 损伤修复和防止 DNA 损伤、抗凋亡作用、抑制药物流入或增加药物流出。代谢功能的上调和新的非代谢功能的获得会导致支持肿瘤发生的生物效应：促进肿瘤的发生、刺激肿瘤细胞增殖和原发性肿瘤的生长、诱导上皮-间质转化、自噬和转移、免疫抑制效应、诱导耐药性以及对肿瘤附属细胞的影响。这些作用对肿瘤患者的预后产生了负面影响。有鉴于此，肿瘤相关糖酵解成为抗肿瘤药物研发的关注目标也就不足为奇了。然而，迄今为止，糖酵解抑制剂的临床效果并不尽如人意。在这篇综述中，我们提出了一些方法，可以绕过迄今为止在使用糖酵解抑制剂进行治疗时遇到的一些困难。

{"title":"The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities","authors":"Marco Cordani , Federica Michetti , Ali Zarrabi , Atefeh Zarepour , Cristiano Rumio , Raffaele Strippoli , Fabrizio Marcucci","doi":"10.1016/j.neo.2024.101076","DOIUrl":"10.1016/j.neo.2024.101076","url":null,"abstract":"<div><div>Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as “moonlighting” functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101076"},"PeriodicalIF":4.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epigenetic DNA modifications and vitamin C in prostate cancer and benign prostatic hyperplasia: Exploring similarities, disparities, and pathogenic implications 前列腺癌和良性前列腺增生中的表观遗传 DNA 修饰和维生素 C：探索相似性、差异性和致病影响。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-10-29 DOI: 10.1016/j.neo.2024.101079

Jolanta Guz , Ewelina Zarakowska , Pawel Mijewski , Aleksandra Wasilow , Fabian Lesniewski , Marek Foksinski , Bartosz Brzoszczyk , Piotr Jarzemski , Daniel Gackowski , Ryszard Olinski

Objectives

Benign Prostatic Hyperplasia (BPH) and Prostate Cancer (PC) are very common pathologies among aging men. Both disorders involve aberrant cell division and differentiation within the prostate gland. However, the direct link between these two disorders still remains controversial. A plethora of works have demonstrated that inflammation is a major causative factor in both pathologies. Another key factor involved in PC development is DNA methylation and hydroxymethylation.

Methods

A broad spectrum of parameters, including epigenetic DNA modifications and 8-oxo-7,8-dihydro-2′-deoxyguanosine, was analyzed by two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry in tissues of BPH, PC, and marginal one, as well as in leukocytes of the patients and the control group. In the same material, the expression of TETs and TDG genes was measured using RT-qPCR. Additionally, vitamin C was quantified in the blood plasma and within cells (leukocytes and prostate tissues).

Results

Unique patterns of DNA modifications and intracellular vitamin C (iVC) in BPH and PC tissues, as well as in leukocytes, were found in comparison with control samples. The majority of the alterations were more pronounced in leukocytes than in the prostate tissues.

Conclusions

Characteristic DNA methylation/hydroxymethylation and iVC profiles have been observed in both PC and BPH, suggesting potential shared molecular pathways between the two conditions. As a fraction of leukocytes may be recruited to the pathological tissues and can migrate back into the circulation/blood, the observed alterations in leukocytes may reflect dynamic changes associated with the PC development, suggesting their potential utility as early markers of prostate cancer development.

目的：良性前列腺增生症（BPH）和前列腺癌（PC）是老年男性中非常常见的病症。这两种疾病都涉及前列腺内异常的细胞分裂和分化。然而，这两种疾病之间的直接联系仍然存在争议。大量研究表明，炎症是这两种病症的主要致病因素。参与 PC 发病的另一个关键因素是 DNA 甲基化和羟甲基化：方法：采用二维超高效液相色谱-串联质谱法分析了良性前列腺增生症、PC 和边缘型 PC 组织以及患者和对照组白细胞中的一系列参数，包括表观遗传 DNA 修饰和 8-氧代-7,8-二氢-2'-脱氧鸟苷。在相同的材料中，使用 RT-qPCR 测量了 TETs 和 TDG 基因的表达。此外，还对血浆和细胞（白细胞和前列腺组织）中的维生素 C 进行了量化：结果：与对照样本相比，发现前列腺增生症和前列腺癌组织以及白细胞中的 DNA 修饰和细胞内维生素 C (iVC) 具有独特的模式。大多数改变在白细胞中比在前列腺组织中更明显：结论：在 PC 和前列腺增生症中都观察到了特征性的 DNA 甲基化/羟甲基化和 iVC 图谱，这表明这两种病症之间可能存在共同的分子途径。由于一部分白细胞可能被招募到病理组织中，并可迁移回血液循环，因此观察到的白细胞变化可能反映了与 PC 发展相关的动态变化，这表明白细胞有可能成为前列腺癌发展的早期标志物。

{"title":"Epigenetic DNA modifications and vitamin C in prostate cancer and benign prostatic hyperplasia: Exploring similarities, disparities, and pathogenic implications","authors":"Jolanta Guz , Ewelina Zarakowska , Pawel Mijewski , Aleksandra Wasilow , Fabian Lesniewski , Marek Foksinski , Bartosz Brzoszczyk , Piotr Jarzemski , Daniel Gackowski , Ryszard Olinski","doi":"10.1016/j.neo.2024.101079","DOIUrl":"10.1016/j.neo.2024.101079","url":null,"abstract":"<div><h3>Objectives</h3><div>Benign Prostatic Hyperplasia (BPH) and Prostate Cancer (PC) are very common pathologies among aging men. Both disorders involve aberrant cell division and differentiation within the prostate gland. However, the direct link between these two disorders still remains controversial. A plethora of works have demonstrated that inflammation is a major causative factor in both pathologies. Another key factor involved in PC development is DNA methylation and hydroxymethylation.</div></div><div><h3>Methods</h3><div>A broad spectrum of parameters, including epigenetic DNA modifications and 8-oxo-7,8-dihydro-2′-deoxyguanosine, was analyzed by two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry in tissues of BPH, PC, and marginal one, as well as in leukocytes of the patients and the control group. In the same material, the expression of <em>TETs</em> and <em>TDG</em> genes was measured using RT-qPCR. Additionally, vitamin C was quantified in the blood plasma and within cells (leukocytes and prostate tissues).</div></div><div><h3>Results</h3><div>Unique patterns of DNA modifications and intracellular vitamin C (iVC) in BPH and PC tissues, as well as in leukocytes, were found in comparison with control samples. The majority of the alterations were more pronounced in leukocytes than in the prostate tissues.</div></div><div><h3>Conclusions</h3><div>Characteristic DNA methylation/hydroxymethylation and iVC profiles have been observed in both PC and BPH, suggesting potential shared molecular pathways between the two conditions. As a fraction of leukocytes may be recruited to the pathological tissues and can migrate back into the circulation/blood, the observed alterations in leukocytes may reflect dynamic changes associated with the PC development, suggesting their potential utility as early markers of prostate cancer development.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101079"},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Systematic analysis of human colorectal cancer scRNA-seq revealed limited pro-tumoral IL-17 production potential in gamma delta T cells 对人类结直肠癌 scRNA-seq 的系统分析显示，γ δ T 细胞产生促肿瘤 IL-17 的潜力有限。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-10-24 DOI: 10.1016/j.neo.2024.101072

Ran Ran , Martin Trapecar , Douglas K. Brubaker

Gamma delta T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin-17 (IL-17) within the tumor microenvironment of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including poised effector-like T cells, tissue-resident memory T cells, progenitor exhausted-like T cells, and exhausted T cells, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. We proposed anti-tumor γδ T effector cells may arise from tissue-resident progenitor cells based on the trajectory analysis. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology.

γδT细胞具有细胞毒性，在抗肿瘤免疫中发挥着重要作用。然而，γδT 细胞在结直肠癌（CRC）肿瘤微环境中产生促致癌白细胞介素-17（IL-17）的作用和程度仍存在争议。在这项研究中，我们重新分析了已发表的 9 个人类 CRC 全组织单细胞 RNA 测序数据集，在 165 名人类 CRC 患者的肿瘤组织或邻近正常组织的 951 785 个细胞总数中鉴定出了 18 483 个 γδ T 细胞。我们的研究结果证实，肿瘤浸润的 γδ T 细胞在肿瘤和邻近正常组织中都表现出高度的细胞毒性相关转录，但关键的是，没有一个 γδ T 细胞集群显示出产生 IL-17 的潜能。我们还发现了各种γδT细胞亚群，包括蓄势待发的效应样T细胞、组织驻留记忆T细胞、衰竭样T细胞祖细胞和衰竭T细胞，并注意到与正常区域的T细胞相比，肿瘤浸润的γδT细胞中细胞毒性分子的表达增加。根据轨迹分析，我们提出抗肿瘤γδT效应细胞可能来自组织驻留的祖细胞。我们的研究表明，CRC 中的γδ T 细胞主要作为细胞毒性效应细胞而非 IL-17 生成细胞发挥作用，这减轻了人们对其在 CRC 中潜在促肿瘤作用的担忧，凸显了准确描述这些细胞对癌症免疫疗法研究的重要性，以及在癌症免疫学研究中小鼠和人类免疫系统之间不可忽视的跨物种差异。

{"title":"Systematic analysis of human colorectal cancer scRNA-seq revealed limited pro-tumoral IL-17 production potential in gamma delta T cells","authors":"Ran Ran , Martin Trapecar , Douglas K. Brubaker","doi":"10.1016/j.neo.2024.101072","DOIUrl":"10.1016/j.neo.2024.101072","url":null,"abstract":"<div><div>Gamma delta T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin-17 (IL-17) within the tumor microenvironment of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including poised effector-like T cells, tissue-resident memory T cells, progenitor exhausted-like T cells, and exhausted T cells, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. We proposed anti-tumor γδ T effector cells may arise from tissue-resident progenitor cells based on the trajectory analysis. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101072"},"PeriodicalIF":4.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RRM2 inhibition alters cell cycle through ATM/Rb/E2F1 pathway in atypical teratoid rhabdoid tumor 抑制 RRM2 可通过 ATM/Rb/E2F1 通路改变非典型畸胎性横纹肌瘤的细胞周期。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-10-21 DOI: 10.1016/j.neo.2024.101075

Le Hien Giang , Kuo-Sheng Wu , Wei-Chung Lee , Shing-Shung Chu , Anh Duy Do , Man-Hsu Huang , Yu-Ling Lin , Chia-Ling Hsieh , Shian-Ying Sung , Yun Yen , Tai-Tong Wong , Che-Chang Chang

Background

Atypical teratoid rhabdoid tumor (ATRT) is an aggressive brain tumor that mainly affects young children. Our recent study reported a promising therapeutic strategy to trigger DNA damage, impede homologous recombination repair, and induce apoptosis in ATRT cells by targeting ribonucleotide reductase regulatory subunit M2 (RRM2). COH29, an inhibitor of RRM2, effectively reduced tumor growth and prolonged survival in vivo. Herein, we explored the underlying mechanisms controlling these functions to improve the clinical applicability of COH29 in ATRT.

Methods

Molecular profiling of ATRT patients and COH29-treated cells was analyzed to identify the specific signaling pathways, followed by validation using a knockdown system, flow cytometry, q-PCR, and western blot.

Results

Elevated E2F1 and its signaling pathway were correlated with poor prognosis. RRM2 inhibition induced DNA damage and activated ATM, which reduced Rb phosphorylation to promote Rb-E2F1 interaction and hindered E2F1 functions. E2F1 activity suppression led to decreased E2F1-dependent target expressions, causing cell cycle arrest in the G1 phase, decreased S phase cells, and blocked DNA damage repair.

Conclusion

Our study highlights the role of ATM/Rb/E2F1 pathway in controlling cell cycle arrest and apoptosis in response to RRM2 inhibition-induced DNA damage. This provides insight into the therapeutic benefits of COH29 and suggests targeting this pathway as a potential treatment for ATRT.

背景：非典型畸形横纹肌瘤（ATRT）是一种侵袭性脑肿瘤，主要影响幼儿。我们最近的研究报告了一种很有前景的治疗策略，即通过靶向核糖核苷酸还原酶调节亚基 M2（RRM2）引发 DNA 损伤、阻碍同源重组修复并诱导 ATRT 细胞凋亡。RRM2抑制剂COH29能有效降低肿瘤生长并延长体内存活时间。在此，我们探讨了控制这些功能的潜在机制，以提高 COH29 在 ATRT 中的临床适用性：方法：分析 ATRT 患者和 COH29 处理细胞的分子谱，以确定特定的信号通路，然后使用基因敲除系统、流式细胞术、q-PCR 和 Western 印迹进行验证：结果：E2F1及其信号通路的升高与预后不良相关。抑制RRM2可诱导DNA损伤并激活ATM，从而减少Rb磷酸化，促进Rb-E2F1相互作用，阻碍E2F1功能的发挥。E2F1活性抑制导致E2F1依赖性靶点表达减少，导致细胞周期停滞在G1期，S期细胞减少，DNA损伤修复受阻：我们的研究强调了ATM/Rb/E2F1通路在RRM2抑制诱导的DNA损伤中控制细胞周期停滞和细胞凋亡的作用。结论：我们的研究强调了ATM/Rb/E2F1通路在RRM2抑制诱导的DNA损伤中控制细胞周期停滞和细胞凋亡的作用，这为COH29的治疗效果提供了启示，并建议将该通路作为治疗ATRT的潜在靶点。

{"title":"RRM2 inhibition alters cell cycle through ATM/Rb/E2F1 pathway in atypical teratoid rhabdoid tumor","authors":"Le Hien Giang , Kuo-Sheng Wu , Wei-Chung Lee , Shing-Shung Chu , Anh Duy Do , Man-Hsu Huang , Yu-Ling Lin , Chia-Ling Hsieh , Shian-Ying Sung , Yun Yen , Tai-Tong Wong , Che-Chang Chang","doi":"10.1016/j.neo.2024.101075","DOIUrl":"10.1016/j.neo.2024.101075","url":null,"abstract":"<div><h3>Background</h3><div>Atypical teratoid rhabdoid tumor (ATRT) is an aggressive brain tumor that mainly affects young children. Our recent study reported a promising therapeutic strategy to trigger DNA damage, impede homologous recombination repair, and induce apoptosis in ATRT cells by targeting ribonucleotide reductase regulatory subunit M2 (RRM2). COH29, an inhibitor of RRM2, effectively reduced tumor growth and prolonged survival in vivo. Herein, we explored the underlying mechanisms controlling these functions to improve the clinical applicability of COH29 in ATRT.</div></div><div><h3>Methods</h3><div>Molecular profiling of ATRT patients and COH29-treated cells was analyzed to identify the specific signaling pathways, followed by validation using a knockdown system, flow cytometry, q-PCR, and western blot.</div></div><div><h3>Results</h3><div>Elevated E2F1 and its signaling pathway were correlated with poor prognosis. RRM2 inhibition induced DNA damage and activated ATM, which reduced Rb phosphorylation to promote Rb-E2F1 interaction and hindered E2F1 functions. E2F1 activity suppression led to decreased E2F1-dependent target expressions, causing cell cycle arrest in the G1 phase, decreased S phase cells, and blocked DNA damage repair.</div></div><div><h3>Conclusion</h3><div>Our study highlights the role of ATM/Rb/E2F1 pathway in controlling cell cycle arrest and apoptosis in response to RRM2 inhibition-induced DNA damage. This provides insight into the therapeutic benefits of COH29 and suggests targeting this pathway as a potential treatment for ATRT.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101075"},"PeriodicalIF":4.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Specifying the choice of EGFR-TKI based on brain metastatic status for advanced NSCLC with EGFR p.L861Q mutation 针对表皮生长因子受体 p.L861Q 突变的晚期 NSCLC，根据脑转移状态明确表皮生长因子受体-TKI 的选择。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2024-10-19 DOI: 10.1016/j.neo.2024.101073

Lan-Lan Pang , Wei-Tao Zhuang , Jun-Jun Li , Bing Li , Yi-Hua Huang , Jun Liao , Meng-Di Li , Li Zhang , Wen-Feng Fang

Background

In-depth insight into the genomic features of the uncommon EGFR p.L861Q mutant NSCLC is scarcely performed, and no consensus on the preferred treatment strategy has been established. Moreover, the therapeutic implications of EGFR-TKI stratified by clinical and molecular features remained largely unknown.

Methods

A multi-center NGS database comprising 44,993 NSCLC samples was utilized for the genomic landscape profiling of EGFR p.L861Q mutation. Furthermore, a real-world cohort of 207 patients harboring EGFR p.L861Q mutation with complete treatment history was curated for comprehensive clinical analysis.

Results

L861Q is prevalent in approximately 2.1% of EGFR-mutated NSCLC and is typically co-mutated with EGFR p.G719X on the same allele (20%) and exhibits co-occurrent EGFR copy number amplification in approximately 17% of cases. In the first-line setting, afatinib and third-generation EGFR-TKI have been shown to yield notably superior treatment outcomes compared to first-generation EGFR-TKI (1^st vs.2^nd vs.3^rd generations, ORR: 15.8% vs.56.5% vs.46.7%, P=0.01; median PFS: 6.4 vs.13.5 vs.15.1 months, P=0.002). This finding consistently held for patients without CNS metastases (1^st vs.2^nd vs.3^rd generations, median PFS:6.0 vs.18.2 vs.14.1 months, P=0.003). In contrast, third-generation EGFR-TKI demonstrated superior efficacy compared to afatinib or first-generation TKI among the subgroup of brain metastasis (Pooled 1^st/2^nd-generation vs.3^rd-generation TKI, brain ORR:0.00% vs.33.33%; median PFS:7.9 vs.19.3 months, P=0.021). Additional concurrent EGFR mutations or EGFR amplification did not yield a discernible impact on the efficacy of EGFR-TKI.

Conclusions

The present study comprehensively elucidates the molecular features of EGFR p.L861Q mutation and underscores the optimal therapeutic choice of first-line EGFR-TKI based on brain metastatic status.

背景：对不常见的表皮生长因子受体（EGFR）p.L861Q突变型NSCLC基因组特征的深入研究很少，对首选治疗策略尚未达成共识。此外，根据临床和分子特征对 EGFR-TKI 进行分层的治疗意义在很大程度上仍不为人所知：方法：多中心 NGS 数据库包含 44993 份 NSCLC 样本，用于 EGFR p.L861Q 突变的基因组图谱分析。此外，还对 207 例携带表皮生长因子受体 p.L861Q 突变且有完整治疗史的患者组成的真实世界队列进行了综合临床分析：L861Q在约2.1%的表皮生长因子受体突变的NSCLC中普遍存在，通常与表皮生长因子受体p.G719X在同一等位基因上共突变（20%），约17%的病例同时存在表皮生长因子受体拷贝数扩增。在一线治疗中，与第一代 EGFR-TKI 相比，阿法替尼和第三代 EGFR-TKI 的治疗效果显著优于第一代 EGFR-TKI（第一代与第二代与第三代相比，ORR：15.8% vs.56.5% vs.46.7%, P=0.01；中位 PFS：6.4 vs.13.5 vs.15.1 个月，P=0.002）。这一结果在没有中枢神经系统转移的患者中也一直存在（第一代与第二代与第三代相比，中位生存期：6.0 个月与 18.2 个月与 14.1 个月相比，P=0.003）。相比之下，在脑转移亚组中，第三代EGFR-TKI的疗效优于阿法替尼或第一代TKI（第1/2代与第3代TKI汇总，脑ORR：0.00% vs.33.33%; 中位PFS：7.9个月 vs.19.3 个月，P=0.021）。其他并发的表皮生长因子受体突变或表皮生长因子受体扩增对表皮生长因子受体TKI的疗效没有明显影响：本研究全面阐明了表皮生长因子受体（EGFR）p.L861Q突变的分子特征，并强调了基于脑转移状态的一线EGFR-TKI的最佳治疗选择。

{"title":"Specifying the choice of EGFR-TKI based on brain metastatic status for advanced NSCLC with EGFR p.L861Q mutation","authors":"Lan-Lan Pang , Wei-Tao Zhuang , Jun-Jun Li , Bing Li , Yi-Hua Huang , Jun Liao , Meng-Di Li , Li Zhang , Wen-Feng Fang","doi":"10.1016/j.neo.2024.101073","DOIUrl":"10.1016/j.neo.2024.101073","url":null,"abstract":"<div><h3>Background</h3><div>In-depth insight into the genomic features of the uncommon EGFR p.L861Q mutant NSCLC is scarcely performed, and no consensus on the preferred treatment strategy has been established. Moreover, the therapeutic implications of EGFR-TKI stratified by clinical and molecular features remained largely unknown.</div></div><div><h3>Methods</h3><div>A multi-center NGS database comprising 44,993 NSCLC samples was utilized for the genomic landscape profiling of EGFR p.L861Q mutation. Furthermore, a real-world cohort of 207 patients harboring EGFR p.L861Q mutation with complete treatment history was curated for comprehensive clinical analysis.</div></div><div><h3>Results</h3><div>L861Q is prevalent in approximately 2.1% of EGFR-mutated NSCLC and is typically co-mutated with EGFR p.G719X on the same allele (20%) and exhibits co-occurrent EGFR copy number amplification in approximately 17% of cases. In the first-line setting, afatinib and third-generation EGFR-TKI have been shown to yield notably superior treatment outcomes compared to first-generation EGFR-TKI (1<sup>st</sup> vs.2<sup>nd</sup> vs.3<sup>rd</sup> generations, ORR: 15.8% vs.56.5% vs.46.7%, <em>P</em>=0.01; median PFS: 6.4 vs.13.5 vs.15.1 months, <em>P</em>=0.002). This finding consistently held for patients without CNS metastases (1<sup>st</sup> vs.2<sup>nd</sup> vs.3<sup>rd</sup> generations, median PFS:6.0 vs.18.2 vs.14.1 months, <em>P</em>=0.003). In contrast, third-generation EGFR-TKI demonstrated superior efficacy compared to afatinib or first-generation TKI among the subgroup of brain metastasis (Pooled 1<sup>st</sup>/2<sup>nd</sup>-generation vs.3<sup>rd</sup>-generation TKI, brain ORR:0.00% vs.33.33%; median PFS:7.9 vs.19.3 months, <em>P</em>=0.021). Additional concurrent EGFR mutations or EGFR amplification did not yield a discernible impact on the efficacy of EGFR-TKI.</div></div><div><h3>Conclusions</h3><div>The present study comprehensively elucidates the molecular features of EGFR p.L861Q mutation and underscores the optimal therapeutic choice of first-line EGFR-TKI based on brain metastatic status.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101073"},"PeriodicalIF":4.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neoplasia最新文献

Background

Methods

Results

Conclusion

Objectives

Methods

Results

Conclusions

Background

Methods

Results

Conclusion

Background

Methods

Results

Conclusions