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Challenges in validation of combination treatment strategies for CRC using patient-derived organoids 利用源自患者的器官组织验证 CRC 综合治疗策略面临的挑战
IF 11.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-11 DOI: 10.1186/s13046-024-03173-x
Valentin Benboubker, George M. Ramzy, Sacha Jacobs, Patrycja Nowak-Sliwinska
Patient-derived organoids (PDOs) established from tissues from various tumor types gave the foundation of ex vivo models to screen and/or validate the activity of many cancer drug candidates. Due to their phenotypic and genotypic similarity to the tumor of which they were derived, PDOs offer results that effectively complement those obtained from more complex models. Yet, their potential for predicting sensitivity to combination therapy remains underexplored. In this review, we discuss the use of PDOs in both validation and optimization of multi-drug combinations for personalized treatment strategies in CRC. Moreover, we present recent advancements in enriching PDOs with diverse cell types, enhancing their ability to mimic the complexity of in vivo environments. Finally, we debate how such sophisticated models are narrowing the gap in personalized medicine, particularly through immunotherapy strategies and discuss the challenges and future direction in this promising field.
根据不同肿瘤类型的组织建立的患者衍生器官组织(PDOs)为体内外模型奠定了基础,可用于筛选和/或验证许多候选抗癌药物的活性。由于其表型和基因型与原发肿瘤相似,患者衍生器官组织提供的结果可有效补充从更复杂的模型中获得的结果。然而,它们在预测联合疗法敏感性方面的潜力仍未得到充分开发。在这篇综述中,我们将讨论 PDOs 在验证和优化 CRC 个性化治疗策略的多种药物组合中的应用。此外,我们还介绍了在用不同细胞类型丰富 PDOs 方面的最新进展,从而增强其模拟体内环境复杂性的能力。最后,我们讨论了这种复杂的模型如何缩小了个性化医疗的差距,特别是通过免疫疗法策略,并讨论了这一前景广阔的领域所面临的挑战和未来的发展方向。
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引用次数: 0
Correction: Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy 更正:新型工程IL-2 Nemvaleukin alfa与PD1检查点阻断相结合可增强放疗的全身抗肿瘤反应
IF 11.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-10 DOI: 10.1186/s13046-024-03183-9
Kewen He, Nahum Puebla-Osorio, Hampartsoum B. Barsoumian, Duygu Sezen, Zahid Rafq, Thomas S. Riad, Yun Hu, Ailing Huang, Tifany A. Voss, Claudia S. Kettlun Leyton, Lily Jae Schuda, Ethan Hsu, Joshua Heiber, Maria-Angelica Cortez, James W. Welsh
<p><b>Correction: J Exp Clin Cancer Res 43, 251 (2024)</b></p><p><b>https://doi.org/10.1186/s13046-024-03165-x</b></p><p>Following publication of the original article [1], the authors found an error in the affiliation of the 5th author, Zahid Rafiq. He was mistakenly assign to Affiliation 1. The details are given below:</p><p><b>Incorrect affiliation</b>:</p><p><sup>1</sup> Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.</p><p><b>Correct affiliation</b>:</p><p><sup>2</sup> Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.</p><p>This correction does not affect the overall result or conclusion of the article. The original article [1] has been corrected.</p><ol data-track-component="outbound reference" data-track-context="references section"><li data-counter="1."><p>He K, Puebla-Osorio N, Barsoumian HB, et al. Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy. J Exp Clin Cancer Res. 2024;43:251. https://doi.org/10.1186/s13046-024-03165-x.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-download-medium" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China</p><p>Kewen He</p></li><li><p>Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA</p><p>Kewen He, Nahum Puebla-Osorio, Hampartsoum B. Barsoumian, Duygu Sezen, Zahid Rafq, Thomas S. Riad, Yun Hu, Ailing Huang, Tifany A. Voss, Claudia S. Kettlun Leyton, Lily Jae Schuda, Ethan Hsu, Maria-Angelica Cortez & James W. Welsh</p></li><li><p>Department of Radiation Oncology, Koç University School of Medicine, Istanbul, Turkey</p><p>Duygu Sezen</p></li><li><p>Mural Oncology PLC, Waltham, MA, USA</p><p>Joshua Heiber</p></li></ol><span>Authors</span><ol><li><span>Kewen He</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Nahum Puebla-Osorio</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Hampartsoum B. Barsoumian</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Duygu Sezen</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></
更正:J Exp Clin Cancer Res 43, 251 (2024)https://doi.org/10.1186/s13046-024-03165-xFollowing 原文[1]发表后,作者发现第 5 位作者扎希德-拉菲克(Zahid Rafiq)的所属单位有误。他被错误地分配到了所属单位 1。详情如下:错误单位:1 Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, Shandong, China.正确单位:2 Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.此更正不影响文章的整体结果或结论。He K, Puebla-Osorio N, Barsoumian HB, et al. Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy.J Exp Cliner Cancer Res. 2024;43:251. https://doi.org/10.1186/s13046-024-03165-x.文章 CAS PubMed PubMed Central Google Scholar 下载参考文献作者及工作单位山东第一医科大学、山东省医学科学院放射肿瘤学系,山东省肿瘤医院及研究所,山东济南Kewen He德克萨斯大学 MD 安德森癌症中心放射肿瘤学部,美国德克萨斯州休斯顿Kewen He, Nahum Puebla-Osorio, Hampartsoum B.Barsoumian、Duygu Sezen、Zahid Rafq、Thomas S. Riad、胡云、黄爱玲、Tifany A. Voss、Claudia S. Kettlun Leyton、Lily Jae Schuda、Ethan Hsu、Maria-Angelica Cortez &amp; James W. Welsh放疗肿瘤学系WelshDepartment of Radiation Oncology, Koç University School of Medicine, Istanbul, TurkeyDuygu SezenMural Oncology PLC, Waltham, MA, USAJoshua HeiberAuthorsKewen He查看作者发表的文章您也可以在PubMed Google Scholar中搜索该作者Nahum Puebla-Osorio查看作者发表的文章您也可以在PubMed Google Scholar中搜索该作者Hampartsoum B.Barsoumian查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Duygu Sezen查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Zahid Rafq查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Thomas S. Riad查看作者发表的作品RiadView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Yun HuView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Ailing HuangView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Tifany A. VossView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Claudia S.Kettlun LeytonView作者发表作品您也可以在PubMed Google Scholar中搜索该作者Lily Jae SchudaView作者发表作品您也可以在PubMed Google Scholar中搜索该作者Ethan HsuView作者发表作品您也可以在PubMed Google Scholar中搜索该作者Joshua HeiberView作者发表作品您也可以在PubMed Google Scholar中搜索该作者Maria-Angelica CortezView作者发表作品您也可以在PubMed Google Scholar中搜索该作者James W.Welsh查看作者发表的文章您也可以在PubMed Google Scholar中搜索该作者通讯作者:Kewen He或James W. Welsh.出版者注Springer Nature对出版地图中的管辖权主张和机构隶属关系保持中立。原文的在线版本可在https://doi.org/10.1186/s13046-024-03165-x.开放存取 本文采用知识共享署名 4.0 国际许可协议进行许可,该协议允许以任何媒介或格式使用、共享、改编、分发和复制,只要您适当注明原作者和来源,提供知识共享许可协议的链接,并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中,除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中,且您打算使用的材料不符合法律规定或超出许可使用范围,则您需要直接从版权所有者处获得许可。要查看该许可的副本,请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明,否则知识共享公共领域专用免责声明 (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据。转载与许可引用本文He, K., Puebla-Osorio, N., Barsoumian, H.B. et al. Correction:新型工程IL-2 Nemvaleukin alfa联合PD1检查点阻断增强了放疗的全身抗肿瘤反应。J Exp Cliner Cancer Res 43, 256 (2024). https://doi.org/10.
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引用次数: 0
Membrane RRM2-positive cells represent a malignant population with cancer stem cell features in intrahepatic cholangiocarcinoma. 膜 RRM2 阳性细胞代表了肝内胆管癌中具有癌干细胞特征的恶性细胞群。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-06 DOI: 10.1186/s13046-024-03174-w
Yongzhi Zhao, Shuting Xue, Danduo Wei, Jianjuan Zhang, Nachuan Zhang, Liping Mao, Niya Liu, Lei Zhao, Jianing Yan, Yifan Wang, Xiujun Cai, Saiyong Zhu, Stephanie Roessler, Junfang Ji

Background: Intrahepatic cholangiocarcinoma (iCCA) is one of the most lethal malignancies and highly heterogeneous. We thus aimed to identify and characterize iCCA cell subpopulations with severe malignant features.

Methods: Transcriptomic datasets from three independent iCCA cohorts (iCCA cohorts 1-3, n = 382) and formalin-fixed and paraffin-embedded tissues from iCCA cohort 4 (n = 31) were used. An unbiased global screening strategy was established, including the transcriptome analysis with the activated malignancy/stemness (MS) signature in iCCA cohorts 1-3 and the mass spectrometry analysis of the sorted stemness reporter-positive iCCA cells. A group of cellular assays and subcutaneous tumor xenograft assay were performed to investigate functional roles of the candidate. Immunohistochemistry was performed in iCCA cohort 4 to examine the expression and localization of the candidate. Molecular and biochemical assays were used to evaluate the membrane localization and functional protein domains of the candidate. Cell sorting was performed and the corresponding cellular molecular assays were utilized to examine cancer stem cell features of the sorted cells.

Results: The unbiased global screening identified RRM2 as the top candidate, with a significantly higher level in iCCA patients with the MS signature activation and in iCCA cells positive for the stemness reporter. Consistently, silencing RRM2 significantly suppressed iCCA malignancy phenotypes both in vitro and in vivo. Moreover, immunohistochemistry in tumor tissues of iCCA patients revealed an unreported cell membrane localization of RRM2, in contrast to its usual cytoplasmic localization. RRM2 cell membrane localization was then confirmed in iCCA cells via immunofluorescence with or without cell membrane permeabilization, cell fractionation assay and cell surface biotinylation assay. Meanwhile, an unclassical signal peptide and a transmembrane domain of RRM2 were revealed experimentally. They were essential for RRM2 trafficking to cell membrane via the conventional endoplasmic reticulum (ER)-Golgi secretory pathway. Furthermore, the membrane RRM2-positive iCCA cells were successfully sorted. These cells possessed significant cancer stem cell malignant features including cell differentiation ability, self-renewal ability, tumor initiation ability, and stemness/malignancy gene signatures. Patients with membrane RRM2-positive iCCA cells had poor prognosis.

Conclusions: RRM2 had an alternative cell membrane localization. The membrane RRM2-positive iCCA cells represented a malignant subpopulation with cancer stem cell features.

背景:肝内胆管癌(iCCA)是最致命的恶性肿瘤之一,具有高度异质性。因此,我们旨在鉴定具有严重恶性特征的 iCCA 细胞亚群并确定其特征:我们使用了来自三个独立 iCCA 队列(iCCA 队列 1-3,n = 382)的转录组数据集和来自 iCCA 队列 4(n = 31)的福尔马林固定和石蜡包埋组织。建立了无偏见的整体筛选策略,包括对iCCA 1-3队列中活化的恶性/干性(MS)特征进行转录组分析,以及对分选的干性报告阳性iCCA细胞进行质谱分析。为了研究候选者的功能作用,还进行了一组细胞实验和皮下肿瘤异种移植实验。对 iCCA 队列 4 进行了免疫组化,以检测候选者的表达和定位。分子和生化试验用于评估候选者的膜定位和功能蛋白域。进行了细胞分选,并利用相应的细胞分子测定来检查分选细胞的癌症干细胞特征:无偏见的全局筛选确定RRM2为首选候选蛋白,在具有MS特征激活的iCCA患者和干性报告阳性的iCCA细胞中,RRM2的水平明显较高。同样,沉默RRM2能显著抑制体外和体内的iCCA恶性表型。此外,iCCA 患者肿瘤组织的免疫组化显示,RRM2 的细胞膜定位与通常的细胞质定位不同。随后,在iCCA细胞中通过免疫荧光、细胞膜通透或不通透、细胞分馏试验和细胞表面生物素化试验证实了RRM2的细胞膜定位。同时,实验还发现了RRM2的非经典信号肽和跨膜结构域。它们对于RRM2通过传统的内质网(ER)-高尔基体分泌途径转运至细胞膜至关重要。此外,还成功分选了膜RRM2阳性的iCCA细胞。这些细胞具有明显的癌症干细胞恶性特征,包括细胞分化能力、自我更新能力、肿瘤诱发能力和干性/恶性基因特征。膜RRM2阳性iCCA细胞的患者预后较差:结论:RRM2具有另一种细胞膜定位方式。结论:RRM2具有另一种细胞膜定位方式,膜RRM2阳性iCCA细胞代表了一种具有癌症干细胞特征的恶性亚群。
{"title":"Membrane RRM2-positive cells represent a malignant population with cancer stem cell features in intrahepatic cholangiocarcinoma.","authors":"Yongzhi Zhao, Shuting Xue, Danduo Wei, Jianjuan Zhang, Nachuan Zhang, Liping Mao, Niya Liu, Lei Zhao, Jianing Yan, Yifan Wang, Xiujun Cai, Saiyong Zhu, Stephanie Roessler, Junfang Ji","doi":"10.1186/s13046-024-03174-w","DOIUrl":"10.1186/s13046-024-03174-w","url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (iCCA) is one of the most lethal malignancies and highly heterogeneous. We thus aimed to identify and characterize iCCA cell subpopulations with severe malignant features.</p><p><strong>Methods: </strong>Transcriptomic datasets from three independent iCCA cohorts (iCCA cohorts 1-3, n = 382) and formalin-fixed and paraffin-embedded tissues from iCCA cohort 4 (n = 31) were used. An unbiased global screening strategy was established, including the transcriptome analysis with the activated malignancy/stemness (MS) signature in iCCA cohorts 1-3 and the mass spectrometry analysis of the sorted stemness reporter-positive iCCA cells. A group of cellular assays and subcutaneous tumor xenograft assay were performed to investigate functional roles of the candidate. Immunohistochemistry was performed in iCCA cohort 4 to examine the expression and localization of the candidate. Molecular and biochemical assays were used to evaluate the membrane localization and functional protein domains of the candidate. Cell sorting was performed and the corresponding cellular molecular assays were utilized to examine cancer stem cell features of the sorted cells.</p><p><strong>Results: </strong>The unbiased global screening identified RRM2 as the top candidate, with a significantly higher level in iCCA patients with the MS signature activation and in iCCA cells positive for the stemness reporter. Consistently, silencing RRM2 significantly suppressed iCCA malignancy phenotypes both in vitro and in vivo. Moreover, immunohistochemistry in tumor tissues of iCCA patients revealed an unreported cell membrane localization of RRM2, in contrast to its usual cytoplasmic localization. RRM2 cell membrane localization was then confirmed in iCCA cells via immunofluorescence with or without cell membrane permeabilization, cell fractionation assay and cell surface biotinylation assay. Meanwhile, an unclassical signal peptide and a transmembrane domain of RRM2 were revealed experimentally. They were essential for RRM2 trafficking to cell membrane via the conventional endoplasmic reticulum (ER)-Golgi secretory pathway. Furthermore, the membrane RRM2-positive iCCA cells were successfully sorted. These cells possessed significant cancer stem cell malignant features including cell differentiation ability, self-renewal ability, tumor initiation ability, and stemness/malignancy gene signatures. Patients with membrane RRM2-positive iCCA cells had poor prognosis.</p><p><strong>Conclusions: </strong>RRM2 had an alternative cell membrane localization. The membrane RRM2-positive iCCA cells represented a malignant subpopulation with cancer stem cell features.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146733","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
HSF1 is a prognostic determinant and therapeutic target in intrahepatic cholangiocarcinoma. HSF1 是肝内胆管癌的预后决定因素和治疗靶点。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-06 DOI: 10.1186/s13046-024-03177-7
Antonio Cigliano, Isabella Gigante, Marina Serra, Gianpaolo Vidili, Maria M Simile, Sara Steinmann, Francesco Urigo, Eleonora Cossu, Giovanni M Pes, Maria P Dore, Silvia Ribback, Egle P Milia, Elena Pizzuto, Serena Mancarella, Li Che, Rosa M Pascale, Gianluigi Giannelli, Matthias Evert, Xin Chen, Diego F Calvisi

Background: Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA.

Methods: Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids.

Results: Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells.

Conclusions: The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis.

背景:肝内胆管癌(iCCA)是一种致命的原发性肝肿瘤,其特点是临床侵袭性强、预后差、治疗手段少。因此,迫切需要新的治疗方法来治愈这种疾病。由于越来越多的证据支持热休克因子 1(HSF1)转录因子在各种癌症类型中的致癌特性,我们研究了它在 iCCA 中的致病性和治疗相关性:方法: 在大量 iCCA 标本中评估 HSF1 的水平。方法:在大量 iCCA 标本中评估了 HSF1 的水平,并使用三种已建立的癌基因驱动 iCCA 小鼠模型研究了 HSF1 失活对 iCCA 体内发展的影响。此外,还评估了抑制 HSF1 对 iCCA 细胞系、人 iCCA 癌相关成纤维细胞(hCAFs)和源自患者的器官组织的肿瘤细胞和肿瘤基质的影响:结果:人类浸润前、浸润性和转移性iCCA显示出广泛的HSF1上调,这与患者的不良预后有关。此外,在 AKT/NICD、AKT/YAP 和 AKT/TAZ 小鼠体内注射抑制 HSF1 活性的显性阴性 HSF1(HSF1dn)能显著延缓胆管癌的发生。在 iCCA 细胞系、iCCA hCAFs 和患者衍生的器官组织中,服用 HSF1 抑制剂 KRIBB-11 能明显减少细胞增殖并诱导细胞凋亡。同时使用Bcl-xL/Bcl2/Bcl-w抑制剂ABT-263可大大增加细胞死亡。此外,KRIBB-11还降低了iCCA细胞的线粒体生物能和糖酵解:本研究数据强调了 HSF1 在胆管癌发生过程中的重要致病、预后和治疗作用。
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引用次数: 0
Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers. 如果能吸收,为什么还要制造:细胞外胆固醇吸收及其在乳腺癌和卵巢癌中的重要性综述。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-06 DOI: 10.1186/s13046-024-03172-y
Anna Røssberg Lauridsen, Aikaterini Skorda, Nuggi Ingholt Winther, Marie Lund Bay, Tuula Kallunki

Cholesterol homeostasis is essential for healthy mammalian cells and dysregulation of cholesterol metabolism contributes to the pathogenesis of various diseases including cancer. Cancer cells are dependent on cholesterol. Malignant progression is associated with high cellular demand for cholesterol, and extracellular cholesterol uptake is often elevated in cancer cell to meet its metabolic needs. Tumors take up cholesterol from the blood stream through their vasculature. Breast cancer grows in, and ovarian cancer metastasizes into fatty tissue that provides them with an additional source of cholesterol. High levels of extracellular cholesterol are beneficial for tumors whose cancer cells master the uptake of extracellular cholesterol. In this review we concentrate on cholesterol uptake mechanisms, receptor-mediated endocytosis and macropinocytosis, and how these are utilized and manipulated by cancer cells to overcome their possible intrinsic or pharmacological limitations in cholesterol synthesis. We focus especially on the involvement of lysosomes in cholesterol uptake. Identifying the vulnerabilities of cholesterol metabolism and manipulating them could provide novel efficient therapeutic strategies for treatment of cancers that manifest dependency for extracellular cholesterol.

胆固醇平衡对哺乳动物细胞的健康至关重要,而胆固醇代谢失调则是包括癌症在内的各种疾病的发病机理之一。癌细胞依赖胆固醇。恶性肿瘤的发展与细胞对胆固醇的高需求有关,而癌细胞对细胞外胆固醇的吸收往往会升高,以满足其代谢需求。肿瘤通过血管从血液中吸收胆固醇。乳腺癌生长在脂肪组织中,卵巢癌转移到脂肪组织中,这为它们提供了额外的胆固醇来源。高水平的细胞外胆固醇对肿瘤有益,因为肿瘤细胞能够吸收细胞外胆固醇。在这篇综述中,我们将集中讨论胆固醇摄取机制、受体介导的内吞作用和大蛋白胞吞作用,以及癌细胞如何利用和操纵这些机制来克服胆固醇合成过程中可能存在的内在或药理限制。我们尤其关注溶酶体参与胆固醇摄取的情况。找出胆固醇代谢的薄弱环节并加以控制,可以为治疗对细胞外胆固醇有依赖性的癌症提供新的高效治疗策略。
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引用次数: 0
The dual role of POSTN in maintaining glioblastoma stem cells and the immunosuppressive phenotype of microglia in glioblastoma. POSTN 在维持胶质母细胞瘤干细胞和胶质母细胞瘤小胶质细胞免疫抑制表型方面的双重作用。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-04 DOI: 10.1186/s13046-024-03175-9
Hao Wang, Lin Yao, Jinming Chen, Yanyan Li, Zuopeng Su, Yongsheng Liu, Wen Li, Yun Xiong, Heyang Gao, Xiao Zhang, Youxin Zhou

Background: Glioblastoma (GBM) is an immunosuppressive, universally lethal cancer driven by glioblastoma stem cells (GSCs). The interplay between GSCs and immunosuppressive microglia plays crucial roles in promoting the malignant growth of GBM; however, the molecular mechanisms underlying this crosstalk are unclear. This study aimed to investigate the role of POSTN in maintaining GSCs and the immunosuppressive phenotype of microglia.

Methods: The expression of POSTN in GBM was identified via immunohistochemistry, quantitative real-time PCR, and immunoblotting. Tumorsphere formation assay, Cell Counting Kit-8 assay and immunofluorescence were used to determine the key role of POSTN in GSC maintenance. ChIP-seq and ChIP-PCR were conducted to confirm the binding sequences of β-catenin in the promoter region of FOSL1. Transwell migration assays, developmental and functional analyses of CD4+ T cells, CFSE staining and analysis, enzyme-linked immunosorbent assays and apoptosis detection tests were used to determine the key role of POSTN in maintaining the immunosuppressive phenotype of microglia and thereby promoting the immunosuppressive tumor microenvironment. Furthermore, the effects of POSTN on GSC maintenance and the immunosuppressive phenotype of microglia were investigated in a patient-derived xenograft model and orthotopic glioma mouse model, respectively.

Results: Our findings revealed that POSTN secreted from GSCs promotes GSC self-renewal and tumor growth via activation of the αVβ3/PI3K/AKT/β-catenin/FOSL1 pathway. In addition to its intrinsic effects on GSCs, POSTN can recruit microglia and upregulate CD70 expression in microglia through the αVβ3/PI3K/AKT/NFκB pathway, which in turn promotes Treg development and functionality and supports the formation of an immunosuppressive tumor microenvironment. In both in vitro models and orthotopic mouse models of GBM, POSTN depletion disrupted GSC maintenance, decreased the recruitment of immunosuppressive microglia and suppressed GBM growth.

Conclusion: Our findings reveal that POSTN plays critical roles in maintaining GSCs and the immunosuppressive phenotype of microglia and provide a new therapeutic target for treating GBM.

背景:胶质母细胞瘤(GBM)是一种由胶质母细胞瘤干细胞(GSCs)驱动的免疫抑制性、普遍致命的癌症。胶质母细胞瘤干细胞和免疫抑制性小胶质细胞之间的相互作用在促进胶质母细胞瘤的恶性生长中起着至关重要的作用;然而,这种串扰的分子机制尚不清楚。本研究旨在探讨POSTN在维持GSCs和小胶质细胞免疫抑制表型中的作用:方法:通过免疫组化、实时定量 PCR 和免疫印迹鉴定 POSTN 在 GBM 中的表达。方法:通过免疫组化、定量实时 PCR 和免疫印迹确定了 POSTN 在 GBM 中的表达,并使用肿瘤球形成试验、细胞计数试剂盒-8 试验和免疫荧光确定了 POSTN 在 GSC 维持中的关键作用。通过ChIP-seq和ChIP-PCR确认了β-catenin在FOSL1启动子区域的结合序列。通过Transwell迁移试验、CD4+ T细胞的发育和功能分析、CFSE染色和分析、酶联免疫吸附试验和细胞凋亡检测试验,确定了POSTN在维持小胶质细胞的免疫抑制表型,从而促进免疫抑制性肿瘤微环境中的关键作用。此外,还分别在患者来源异种移植模型和正位胶质瘤小鼠模型中研究了POSTN对GSC维持和小胶质细胞免疫抑制表型的影响:结果:我们的研究结果表明,GSCs分泌的POSTN通过激活αVβ3/PI3K/AKT/β-catenin/FOSL1通路促进GSC自我更新和肿瘤生长。除了对GSCs的内在作用外,POSTN还能招募小胶质细胞,并通过αVβ3/PI3K/AKT/NFκB途径上调小胶质细胞中CD70的表达,进而促进Treg的发育和功能,支持免疫抑制性肿瘤微环境的形成。在GBM的体外模型和正位小鼠模型中,POSTN耗竭会破坏GSC的维持,减少免疫抑制性小胶质细胞的招募,并抑制GBM的生长:我们的研究结果表明,POSTN 在维持 GSC 和小胶质细胞免疫抑制表型方面发挥着关键作用,并为治疗 GBM 提供了一个新的治疗靶点。
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引用次数: 0
Multibiomarker panels in liquid biopsy for early detection of pancreatic cancer - a comprehensive review. 液体活检中用于胰腺癌早期检测的多生物标记物面板--全面综述。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-02 DOI: 10.1186/s13046-024-03166-w
Kim-Lea Reese, Klaus Pantel, Daniel J Smit

Pancreatic ductal adenocarcinoma (PDAC) is frequently detected in late stages, which leads to limited therapeutic options and a dismal overall survival rate. To date, no robust method for the detection of early-stage PDAC that can be used for targeted screening approaches is available. Liquid biopsy allows the minimally invasive collection of body fluids (typically peripheral blood) and the subsequent analysis of circulating tumor cells or tumor-associated molecules such as nucleic acids, proteins, or metabolites that may be useful for the early diagnosis of PDAC. Single biomarkers may lack sensitivity and/or specificity to reliably detect PDAC, while combinations of these circulating biomarkers in multimarker panels may improve the sensitivity and specificity of blood test-based diagnosis. In this narrative review, we present an overview of different liquid biopsy biomarkers for the early diagnosis of PDAC and discuss the validity of multimarker panels.

胰腺导管腺癌(PDAC)常常在晚期才被发现,这导致治疗方案有限,总生存率很低。迄今为止,还没有一种检测早期 PDAC 的可靠方法可用于靶向筛查。液体活检可通过微创方式收集体液(通常是外周血),然后分析循环肿瘤细胞或肿瘤相关分子(如核酸、蛋白质或代谢物),这可能有助于 PDAC 的早期诊断。单一的生物标记物可能缺乏灵敏度和/或特异性,无法可靠地检测出 PDAC,而将这些循环生物标记物组合成多标记物板,可提高基于血液检测诊断的灵敏度和特异性。在这篇叙述性综述中,我们概述了用于早期诊断 PDAC 的不同液体生物标记物,并讨论了多标记物组合的有效性。
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引用次数: 0
Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy. 新型工程IL-2 Nemvaleukin alfa与PD1检查点阻断相结合,可增强放疗的全身抗肿瘤反应。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-02 DOI: 10.1186/s13046-024-03165-x
Kewen He, Nahum Puebla-Osorio, Hampartsoum B Barsoumian, Duygu Sezen, Zahid Rafiq, Thomas S Riad, Yun Hu, Ailing Huang, Tiffany A Voss, Claudia S Kettlun Leyton, Lily Jae Schuda, Ethan Hsu, Joshua Heiber, Maria-Angelica Cortez, James W Welsh

Background: Combining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models.

Methods: Two bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit.

Results: Compared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations.

Conclusion: The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.

背景:将白细胞介素-2(IL-2)与放疗(RT)和免疫检查点阻断(ICB)相结合,已成为解决ICB耐药问题的一种很有前景的方法。然而,传统的IL-2细胞因子疗法因其短暂的半衰期和不良反应而受到限制。RDB 1462是Nemvaleukin alfa的小鼠同源物,它是一种具有中间亲和力的工程化IL-2,可选择性地刺激抗肿瘤CD8 T细胞和NK细胞,同时限制调节性T细胞的扩增。本研究旨在评估RDB 1462、RT和抗PD1联合疗法在小鼠肿瘤模型中的抗肿瘤活性和作用机制:方法:使用 344SQ 亲代细胞系和 344SQ 抗 PD1 细胞系建立了两个双侧肺腺癌小鼠模型。用 RT 治疗原发肿瘤,观察继发肿瘤是否有脱落效应。我们用流式细胞术进行了免疫表型分析,用 NanoString 分析了 770 个免疫相关基因,并进行了 T 细胞受体 (TCR) 重排分析。血清促炎细胞因子标记物通过 23-plex 试剂盒进行分析:结果:与原生IL-2(RDB 1475)相比,RDB 1462表现出更优越的全身抗肿瘤反应,这至少部分归因于后者增强了CD4和CD8 T细胞的水平。我们的研究结果表明,与单药对照组相比,原发性和继发性肿瘤体积大幅缩小,RDB 1462与RT联合治疗的不同给药方案之间存在一定差异。基于血液和肿瘤组织的流式细胞表型分析表明,在联合用药组中,效应记忆CD8和CD4 T细胞增加,免疫抑制细胞减少,同时IL-2、IFN-γ和GM-CSF水平显著增加。转录组学分析和 TCR 测序显示,双重疗法组合具有良好的基因表达和 T 细胞群模式。此外,将抗PD1疗法与RT和RDB 1462结合使用可进一步缩小原发性和继发性肿瘤体积、延长生存期并减少肺转移。对免疫细胞图谱的观察表明,RT与递增剂量的RDB 1462能显著减少肿瘤生长,增加肿瘤特异性免疫细胞群:结论:添加Nemvaleukin疗法可增强对RT单独或与抗PD1联合治疗的反应。
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引用次数: 0
USP36 promotes tumorigenesis and tamoxifen resistance in breast cancer by deubiquitinating and stabilizing ERα. USP36 通过去泛素化和稳定 ERα 促进乳腺癌的肿瘤发生和他莫昔芬抗性。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-31 DOI: 10.1186/s13046-024-03160-2
Ting Zhuang, Shuqing Zhang, Dongyi Liu, Zhongbo Li, Xin Li, Jiaoyan Li, Penghe Yang, Chenmiao Zhang, Jiayao Cui, Mingxi Fu, Fangyu Shen, Lei Yuan, Zhao Zhang, Peng Su, Jian Zhu, Huijie Yang

Background: Breast cancer is the most prevalent cancer in women globally. Over-activated estrogen receptor (ER) α signaling is considered the main factor in luminal breast cancers, which can be effectively managed with selective estrogen receptor modulators (SERMs) like tamoxifen. However, approximately 30-40% of ER + breast cancer cases are recurrent after tamoxifen therapy. This implies that the treatment of breast cancer is still hindered by resistance to tamoxifen. Recent studies have suggested that post-translational modifications of ERα play a significant role in endocrine resistance. The stability of both ERα protein and its transcriptome is regulated by a balance between E3 ubiquitin ligases and deubiquitinases. According to the current knowledge, approximately 100 deubiquitinases are encoded in the human genome, but it remains unclear which deubiquitinases play a critical role in estrogen signaling and endocrine resistance. Thus, decoding the key deubiquitinases that significantly impact estrogen signaling, including the control of ERα expression and stability, is critical for the improvement of breast cancer therapeutics.

Methods: We used several ER positive breast cancer cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model and performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, and luciferase activity assay to investigate the function of USP36 in breast cancer progression and tamoxifen resistance.

Results: In this study, we identify Ubiquitin-specific peptidase 36 (USP36) as a key deubiquitinase involved in ERα signaling and the advancement of breast cancer by deubiquitinases siRNA library screening. In vitro and in vivo studies showed that USP36, but not its catalytically inactive mutant (C131A), could promote breast cancer progression through ERα signaling. Conversely, silencing USP36 inhibited tumorigenesis. In models resistant to endocrine therapy, silencing USP36 destabilized the resistant form of ERα (Y537S) and restored sensitivity to tamoxifen. Molecular studies indicated that USP36 inhibited K48-linked polyubiquitination of ERα and enhanced the ERα transcriptome. It is interesting to note that our results suggest USP36 as a novel biomarker for treatment of breast cancer.

Conclusion: Our study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer.

背景:乳腺癌是全球女性发病率最高的癌症。过度激活的雌激素受体(ER)α信号被认为是腔内乳腺癌的主要因素,它可以通过他莫昔芬等选择性雌激素受体调节剂(SERM)得到有效控制。然而,约有 30%-40% 的 ER + 乳腺癌病例在他莫昔芬治疗后会复发。这意味着乳腺癌的治疗仍然受到他莫昔芬耐药性的阻碍。最近的研究表明,ERα的翻译后修饰在内分泌抵抗中起着重要作用。ERα蛋白及其转录组的稳定性受E3泛素连接酶和去泛素酶之间的平衡调节。据目前所知,人类基因组中编码了约100种去泛素化酶,但仍不清楚哪些去泛素化酶在雌激素信号转导和内分泌抗性中发挥关键作用。因此,解码对雌激素信号转导(包括对ERα表达和稳定性的控制)有重要影响的关键泛素化酶,对于改善乳腺癌治疗至关重要:方法:我们使用了几种ER阳性乳腺癌细胞系、DUB siRNA文库筛选、异种移植模型、内分泌耐药(ERα-Y537S)模型,并进行了免疫印迹、实时PCR、RNA测序、免疫荧光和荧光素酶活性测定,以研究USP36在乳腺癌进展和他莫昔芬耐药中的功能:本研究通过去泛素酶 siRNA 文库筛选,发现泛素特异性肽酶 36(USP36)是参与 ERα 信号转导和乳腺癌进展的关键去泛素酶。体外和体内研究表明,USP36(而非其催化无活性突变体(C131A))可通过ERα信号转导促进乳腺癌的进展。相反,沉默 USP36 则会抑制肿瘤发生。在对内分泌治疗耐药的模型中,沉默 USP36 会破坏 ERα 的耐药形式(Y537S)的稳定性,并恢复对他莫昔芬的敏感性。分子研究表明,USP36 抑制了与 K48 链接的 ERα 多泛素化,并增强了 ERα 的转录组。值得注意的是,我们的研究结果表明 USP36 是治疗乳腺癌的新型生物标记物:我们的研究揭示了抑制 USP36 与他莫昔芬联用可为乳腺癌提供一种潜在疗法的可能性。
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引用次数: 0
Co-delivery of camptothecin and MiR-145 by lipid nanoparticles for MRI-visible targeted therapy of hepatocellular carcinoma. 通过脂质纳米颗粒联合递送喜树碱和 MiR-145,用于肝细胞癌的核磁共振可视靶向治疗。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.1186/s13046-024-03167-9
Jing Rong, Tongtong Liu, Xiujuan Yin, Min Shao, Kun Zhu, Bin Li, Shiqi Wang, Yujie Zhu, Saisai Zhang, Likang Yin, Qi Liu, Xiao Wang, Lei Zhang

Background: Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity.

Methods: Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model.

Results: The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution.

Conclusions: The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.

背景:喜树碱(CPT)是治疗肝细胞癌(HCC)的常用小剂量化疗药物之一,但由于严重的毒性和获得性耐药性,其临床应用受到限制。据报道,化疗与基因治疗相结合是一种有效的策略,既能对抗耐药性,又能使癌细胞对细胞毒性药物敏感。因此,我们假设将 CPT 与 miR-145 结合使用可协同抑制肿瘤增殖并增强抗肿瘤活性:方法:我们开发了乳糖酸(LA)修饰的脂质纳米颗粒(LNPs),在体外和体内将CPT和miR-145共同递送到表达asialoglycoprotein受体的HCC中。我们在体外使用 CCK8、Western 印迹、细胞凋亡和伤口划痕试验评估了 miR-145 和 CPT 的协同抗肿瘤作用,并进一步研究了协同抗肿瘤作用的机制。利用二乙基亚硝胺(DEN)+CCl4诱导的HCC小鼠模型评估了肿瘤抑制效果、安全性评价和MRI可视能力:结果:LA修饰改善了载体对HCC细胞和组织的靶向递送。在体外和体内,LA-CMGL 介导的 miR-145 和 CPT 联合给药比 LA-CPT-L 或 LA-miR-145-L 单独治疗对肿瘤的抑制更有效,而且在治疗期间几乎没有副作用。从机理上讲,miR-145 可能通过靶向 SUMO 特异性肽酶 1(SENP1)介导的己糖激酶(HK2)SUMOylation 和糖酵解途径诱导细胞凋亡,进而使癌细胞对 CPT 敏感。体外和体内试验证实,负载的 Gd-DOTA 是一种有效的 T1 加权造影剂,可用于无创肿瘤检测以及药物输送和生物分布的实时监测:LA-CMGL介导的miR-145和CPT联合给药对HCC具有协同治疗作用。结论:LA-CMGL介导的miR-145和CPT联合给药对HCC具有协同治疗作用,这种新型的磁共振可见主动靶向化疗基因联合给药系统为未来HCC治疗策略的发展提供了科学依据和有益的思路。
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Journal of Experimental & Clinical Cancer Research
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