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Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors. 单次静脉注射溶瘤腺病毒 TILT-123 可使晚期实体瘤患者产生全身肿瘤转导和免疫反应。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-06 DOI: 10.1186/s13046-024-03219-0
Elise Jirovec, Dafne C A Quixabeira, James H A Clubb, Santeri A Pakola, Tatiana Kudling, Victor Arias, Lyna Haybout, Katriina Jalkanen, Tuomo Alanko, Tine Monberg, Amir Khammari, Brigitte Dreno, Inge Marie Svane, Matthew S Block, Daniel A Adamo, Johanna Mäenpää, Claudia Kistler, Suvi Sorsa, Otto Hemminki, Anna Kanerva, João M Santos, Victor Cervera-Carrascon, Akseli Hemminki

Background: A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials.

Methods: Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 109 to 4 × 1012 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period.

Results: Across all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405).

Conclusion: TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation.

Trial registrations: TUNIMO-NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327 . TUNINTIL-NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473 . PROTA-NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318 .

背景:已获批准的溶瘤病毒的一个局限性是需要进行瘤内注射。TILT-123(igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2)是一种嵌合型溶瘤腺病毒,由于其病毒帽修饰和双选择性装置,适合静脉注射。它含有肿瘤坏死α和白细胞介素-2,可促进T细胞活化和淋巴细胞迁移到肿瘤,从而增强抗肿瘤免疫反应。在此,我们将介绍在三项 I 期剂量递增临床试验中单次静脉注射 TILT-123 后的结果:方法:晚期实体瘤患者最初接受单次静脉注射剂量为 3 × 109 至 4 × 1012 的 TILT-123 病毒颗粒(VP)。在基线、治疗后1、16和192小时(7天)采集血液,进行生物利用度和血清分析。在治疗前和治疗后 7 天收集肿瘤活检组织,以分析病毒的存在和免疫效应。在此期间,患者没有接受任何其他癌症疗法:在所有三项试验(TUNIMO、TUNINTIL 和 PROTA)中,共有 52 名患者接受了静脉注射 TILT-123 治疗。总体而言,TILT-123 的耐受性良好,未发现剂量限制性毒性反应。治疗后的肿瘤活检显示病毒基因的表达、TILT-123腺病毒蛋白或DNA的存在以及免疫细胞浸润与基线相比的变化。病毒剂量的增加并未导致肿瘤中病毒检测的增加。治疗后活检证实存在TILT-123的患者中位总生存期更长(280天对190天,P = 0.0405):结论:TILT-123在单次静脉给药后表现出安全性和显著的瘤内免疫调节作用,值得进一步研究:试验注册:TUNIMO-NCT04695327。2021 年 1 月 4 日注册,https://clinicaltrials.gov/study/NCT04695327 。TUNINTIL-NCT04217473.注册时间为 2019 年 12 月 19 日,https://clinicaltrials.gov/study/NCT04217473 。PRTA-NCT05271318。2022 年 2 月 4 日注册,https://clinicaltrials.gov/study/NCT05271318 。
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引用次数: 0
A nanoencapsulated oral formulation of fenretinide promotes local and metastatic breast cancer dormancy in HER2/neu transgenic mice. 芬瑞替尼纳米胶囊口服制剂可促进 HER2/neu 转基因小鼠局部和转移性乳腺癌的休眠。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-05 DOI: 10.1186/s13046-024-03213-6
Maria Laura De Angelis, Federica Francescangeli, Eleonora Aricò, Paola Verachi, Massimo Zucchetti, Cristina Matteo, Elena Petricci, Emanuela Pilozzi, Isabella Orienti, Alessandra Boe, Adriana Eramo, Rachele Rossi, Tiberio Corati, Daniele Macchia, Anna Maria Pacca, Ann Zeuner, Marta Baiocchi

Background: Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC.

Methods: We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice.

Results: Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway.

Conclusion: The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis.

背景:预防和治疗转移性乳腺癌(BC预防和治疗转移性乳腺癌(BC)是一项尚未满足的临床需求。视黄酸衍生物非格列汀(FeR)曾在 I-III 期临床试验中接受过评估,尽管它在临床前模型中具有极佳的耐受性和抗肿瘤活性,但由于生物利用度较低,因此疗效有限。我们最近生成了一种新的铁线肽胶束制剂--Bionanofenretinide(Bio-nFeR),其生物利用度提高,毒性降低,对人类肺癌、结直肠癌和黑色素瘤异种移植物具有很强的抗肿瘤疗效。在本研究中,我们测试了 Bio-nFeR 对转移性 BC 临床前模型的作用:我们使用 BC 细胞系进行细胞活力、细胞周期和迁移能力的体外分析。在体内研究中,我们使用 HER2/neu 转基因小鼠(neuT)作为自发性转移性 BC 的模型。小鼠口服 Bio-nFeR,牺牲时通过组织学和免疫组化对原发性和转移性乳腺肿瘤进行分析。用免疫印迹法分析原发肿瘤中激活的分子通路。干细胞含量通过流式细胞术、免疫印迹法和功能检测(如体内外集落形成和免疫缺陷小鼠第二次移植检测)进行评估:结果:Bio-nFeR 在体外抑制了 neuT BC 细胞的增殖和迁移,对 neuT 小鼠 BC 的发病有显著疗效。重要的是,Bio-nFeR 对转移进展表现出最高的效力,既能抑制转移的发生,也能抑制转移的扩大。Bio-nFeR 的主要作用机制是通过联合诱导抗增殖信号和抑制 mTOR 通路来促进肿瘤休眠:结论:Bio-nFeR 在乳腺癌 neuT 模型中的高效性及其低毒性表明,该制剂是治疗转移性 BC 和辅助治疗高转移风险 BC 患者的潜在候选药物。
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引用次数: 0
Notch1 blockade by a novel, selective anti-Notch1 neutralizing antibody improves immunotherapy efficacy in melanoma by promoting an inflamed TME. 新型选择性抗Notch1中和抗体阻断Notch1可通过促进发炎的TME提高黑色素瘤的免疫治疗效果。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1186/s13046-024-03214-5
Juliano Tiburcio de Freitas, Varsha Thakur, Kathryn M LaPorte, Vijay S Thakur, Brian Flores, Valentina Caicedo, Chioma G E Ajaegbu, Giuseppe Ingrasci, Zoe M Lipman, Keman Zhang, Hong Qiu, Thomas R Malek, Barbara Bedogni

Background: Immune checkpoint inhibitors (ICI) have dramatically improved the life expectancy of patients with metastatic melanoma. However, about half of the patient population still present resistance to these treatments. We have previously shown Notch1 contributes to a non-inflamed TME in melanoma that reduces the response to ICI. Here, we addressed the therapeutic effects of a novel anti-Notch1 neutralizing antibody we produced, alone and in combination with immune checkpoint inhibition in melanoma models.

Methods: Anti-Notch1 was designed to interfere with ligand binding. Mice were immunized with a peptide encompassing EGF-like repeats 11-15 of human Notch1, the minimal required region that allows ligand binding and Notch1 activation. Positive clones were expanded and tested for neutralizing capabilities. Anti-Notch1-NIC was used to determine whether anti-Notch1 was able to reduce Notch1 cleavage; while anti-SNAP23 and BCAT2 were used as downstream Notch1 and Notch2 targets, respectively. K457 human melanoma cells and the YUMM2.1 and 1.7 syngeneic mouse melanoma cells were used. Cell death after anti-Notch1 treatment was determined by trypan blue staining and compared to the effects of the gamma-secretase inhibitor DBZ. 10 mg/kg anti-Notch1 was used for in vivo tumor growth of YUMM2.1 and 1.7 cells. Tumors were measured and processed for flow cytometry using antibodies against major immune cell populations.

Results: Anti-Notch1 selectively inhibited Notch1 but not Notch2; caused significant melanoma cell death in vitro but did not affect normal melanocytes. In vivo, it delayed tumor growth without evident signs of gastro-intestinal toxicities; and importantly promoted an inflamed TME by increasing the cytotoxic CD8+ T cells while reducing the tolerogenic Tregs and MDSCs, resulting in enhanced efficacy of anti-PD-1.

Conclusions: Anti-Notch1 safely exerts anti-melanoma effects and improves immune checkpoint inhibitor efficacy. Thus, anti-Notch1 could represent a novel addition to the immunotherapy repertoire for melanoma.

背景:免疫检查点抑制剂(ICI免疫检查点抑制剂(ICI)大大延长了转移性黑色素瘤患者的寿命。然而,约有一半的患者仍对这些治疗产生抗药性。我们之前已经证明,Notch1 有助于黑色素瘤的非炎症 TME,从而降低对 ICI 的反应。在此,我们探讨了我们生产的新型抗Notch1中和抗体在黑色素瘤模型中单独或与免疫检查点抑制剂联合使用的治疗效果:方法:抗 Notch1 被设计为干扰配体结合。用包含人Notch1的EGF样重复序列11-15的多肽免疫小鼠,这是配体结合和Notch1激活所需的最小区域。对阳性克隆进行扩增并测试其中和能力。抗Notch1-NIC用于确定抗Notch1是否能减少Notch1的裂解;而抗SNAP23和BCAT2则分别作为Notch1和Notch2的下游靶点。研究使用了 K457 人类黑色素瘤细胞以及 YUMM2.1 和 1.7 合成小鼠黑色素瘤细胞。通过胰蓝染色确定抗Notch1处理后的细胞死亡情况,并与γ-分泌酶抑制剂DBZ的效果进行比较。10 mg/kg anti-Notch1用于YUMM2.1和1.7细胞的体内肿瘤生长。使用针对主要免疫细胞群的抗体对肿瘤进行测量和流式细胞术处理:结果:抗 Notch1 可选择性抑制 Notch1,但不能抑制 Notch2;在体外可导致黑色素瘤细胞大量死亡,但不影响正常黑色素细胞。在体内,它能延缓肿瘤生长,且无明显的胃肠道毒性症状;重要的是,它能通过增加细胞毒性 CD8+ T 细胞而减少耐受性 Tregs 和 MDSCs 来促进炎性 TME,从而增强抗 PD-1 的疗效:结论:抗Notch1能安全地发挥抗黑色素瘤作用,并提高免疫检查点抑制剂的疗效。结论:抗Notch1能安全地发挥抗黑色素瘤的作用,并能提高免疫检查点抑制剂的疗效,因此,抗Notch1是黑色素瘤免疫疗法的新成员。
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引用次数: 0
The FGF/FGFR/c-Myc axis as a promising therapeutic target in multiple myeloma. FGF/FGFR/c-Myc轴是多发性骨髓瘤的有望治疗靶点。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1186/s13046-024-03217-2
Arianna Giacomini, Sara Taranto, Giorgia Gazzaroli, Jessica Faletti, Davide Capoferri, Raffaella Marcheselli, Margherita Sciumè, Marco Presta, Antonio Sacco, Aldo M Roccaro

Among blood cancers, multiple myeloma (MM) represents the second most common neoplasm and is characterized by the accumulation and proliferation of monoclonal plasma cells within the bone marrow. Despite the last few decades being characterized by the development of different therapeutic strategies against MM, at present such disease is still considered incurable. Although MM is highly heterogeneous in terms of genetic and molecular subtypes, about 67% of MM cases are associated with abnormal activity of the transcription factor c-Myc, which has so far revealed a protein extremely difficult to target. We have recently demonstrated that activation of fibroblast growth factor (FGF) signaling protects MM cells from oxidative stress-induced apoptosis by stabilizing the oncoprotein c-Myc. Accordingly, secretion of FGF ligands and autocrine activation of FGF receptors (FGFR) is observed in MM cells and FGFR3 genomic alterations represent some 15-20% MM cases and are associated with poor outcome. Thus, FGF/FGFR blockade may represent a promising strategy to indirectly target c-Myc in MM. On this basis, the present review aims at providing an overview of recently explored connections between the FGF/FGFR system and c-Myc oncoprotein, sustaining the therapeutic potential of targeting the FGF/FGFR/c-Myc axis in MM by using inhibitors targeting FGF ligands or FGF receptors. Importantly, the provided findings may represent the rationale for using FDA approved FGFR TK inhibitors (i.e. Pemigatinib, Futibatinib, Erdafitinib) for the treatment of MM patients presenting with an aberrant activation of this axis.

在血癌中,多发性骨髓瘤(MM)是第二大常见肿瘤,其特征是骨髓中单克隆浆细胞的聚集和增殖。尽管在过去的几十年里,针对多发性骨髓瘤开发出了不同的治疗策略,但目前这种疾病仍被认为是不治之症。虽然 MM 在遗传和分子亚型方面具有高度异质性,但约 67% 的 MM 病例与转录因子 c-Myc 的异常活性有关,而迄今为止,c-Myc 蛋白仍是一种极难靶向的蛋白质。我们最近证实,成纤维细胞生长因子(FGF)信号的激活可通过稳定肿瘤蛋白 c-Myc 保护 MM 细胞免受氧化应激诱导的细胞凋亡。因此,在 MM 细胞中可观察到成纤维细胞生长因子配体的分泌和成纤维细胞生长因子受体(FGFR)的自分泌激活,FGFR3 基因组改变约占 MM 病例的 15-20%,并与不良预后有关。因此,阻断成纤维细胞生长因子受体/成纤维细胞生长因子受体可能是在 MM 中间接靶向 c-Myc 的一种有前途的策略。在此基础上,本综述旨在概述最近探索的成纤维细胞生长因子/成纤维细胞生长因子受体系统与 c-Myc 肿瘤蛋白之间的联系,通过使用靶向成纤维细胞生长因子配体或成纤维细胞生长因子受体的抑制剂,维持靶向成纤维细胞生长因子/成纤维细胞生长因子受体/c-Myc 轴的治疗潜力。重要的是,这些发现可能是使用 FDA 批准的 FGFR TK 抑制剂(即 Pemigatinib、Futibatinib、Erdafitinib)治疗出现该轴异常激活的 MM 患者的依据。
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引用次数: 0
Correction: Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming. 更正:胰腺癌启动细胞外泌体信息转移到非癌症启动细胞:CD44v6 在重编程中的重要性。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-31 DOI: 10.1186/s13046-024-03216-3
Zhe Wang, Hanxue Sun, Jan Provaznik, Thilo Hackert, Margot Zöller
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引用次数: 0
Combining ERAP1 silencing and entinostat therapy to overcome resistance to cancer immunotherapy in neuroblastoma. 结合ERAP1沉默和恩替诺特疗法,克服神经母细胞瘤对癌症免疫疗法的耐药性。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-22 DOI: 10.1186/s13046-024-03180-y
Patrizia Tempora, Silvia D'Amico, Paula Gragera, Verena Damiani, Kamila Krol, Valentina Scaldaferri, Kirti Pandey, Shanzou Chung, Valeria Lucarini, Ezio Giorda, Marco Scarsella, Gabriele Volpe, Marco Pezzullo, Cristiano De Stefanis, Valentina D'Oria, Lorenzo De Angelis, Roberto Giovannoni, Maria Antonietta De Ioris, Ombretta Melaiu, Anthony W Purcell, Franco Locatelli, Doriana Fruci

Background: Checkpoint immunotherapy unleashes tumor control by T cells, but it is undermined in non-immunogenic tumors, e.g. with low MHC class I expression and low neoantigen burden, such as neuroblastoma (NB). Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides before loading on MHC class I molecules. Inhibition of ERAP1 results in the generation of new antigens able of inducing potent anti-tumor immune responses. Here, we identify a novel non-toxic combinatorial strategy based on genetic inhibition of ERAP1 and administration of the HDAC inhibitor (HDACi) entinostat that increase the immunogenicity of NB, making it responsive to PD-1 therapy.

Methods: CRISPR/Cas9-mediated gene editing was used to knockout (KO) the ERAP1 gene in 9464D NB cells derived from spontaneous tumors of TH-MYCN transgenic mice. The expression of MHC class I and PD-L1 was evaluated by flow cytometry (FC). The immunopeptidome of these cells was studied by mass spectrometry. Cocultures of splenocytes derived from 9464D bearing mice and tumor cells allowed the assessment of the effect of ERAP1 inhibition on the secretion of inflammatory cytokines and activation and migration of immune cells towards ERAP1 KO cells by FC. Tumor cell killing was evaluated by Caspase 3/7 assay and flow cytometry analysis. The effect of ERAP1 inhibition on the immune content of tumors was analyzed by FC, immunohistochemistry and multiple immunofluorescence.

Results: We found that inhibition of ERAP1 makes 9464D cells more susceptible to immune cell-mediated killing by increasing both the recall and activation of CD4+ and CD8+ T cells and NK cells. Treatment with entinostat induces the expression of MHC class I and PD-L1 molecules in 9464D both in vitro and in vivo. This results in pronounced changes in the immunopeptidome induced by ERAP1 inhibition, but also restrains the growth of ERAP1 KO tumors in vivo by remodelling the tumor-infiltrating T-cell compartment. Interestingly, the absence of ERAP1 in combination with entinostat and PD-1 blockade overcomes resistance to PD-1 immunotherapy and increases host survival.

Conclusions: These findings demonstrate that ERAP1 inhibition combined with HDACi entinostat treatment and PD-1 blockade remodels the immune landscape of a non-immunogenic tumor such as NB, making it responsive to checkpoint immunotherapy.

背景:检查点免疫疗法可释放T细胞对肿瘤的控制作用,但对于非免疫原性肿瘤,如MHC I类低表达和新抗原负荷低的肿瘤,如神经母细胞瘤(NB),这种疗法就会受到破坏。内质网氨肽酶 1(ERAP1)是一种在肽载入 MHC I 类分子之前对其进行修饰的酶。抑制 ERAP1 会产生新的抗原,从而诱导有效的抗肿瘤免疫反应。在这里,我们发现了一种新型无毒组合策略,该策略基于对ERAP1的基因抑制和HDAC抑制剂(HDACi)恩替诺司他的施用,可增加NB的免疫原性,使其对PD-1疗法产生反应:方法:利用 CRISPR/Cas9 介导的基因编辑技术敲除(KO)来自 TH-MYCN 转基因小鼠自发性肿瘤的 9464D NB 细胞中的 ERAP1 基因。流式细胞术(FC)评估了 MHC I 类和 PD-L1 的表达。质谱法研究了这些细胞的免疫肽组。将携带 9464D 的小鼠脾脏细胞与肿瘤细胞共培养,可通过 FC 评估 ERAP1 抑制对炎症细胞因子分泌的影响,以及免疫细胞对 ERAP1 KO 细胞的激活和迁移。Caspase 3/7 检测法和流式细胞术分析评估了肿瘤细胞杀伤作用。通过FC、免疫组化和多重免疫荧光分析了抑制ERAP1对肿瘤免疫成分的影响:结果:我们发现,抑制ERAP1会增加CD4+和CD8+T细胞以及NK细胞的召回和活化,从而使9464D细胞更容易受到免疫细胞介导的杀伤。用恩替诺特治疗可诱导 9464D 细胞在体外和体内表达 MHC I 类和 PD-L1 分子。这不仅导致ERAP1抑制诱导的免疫肽组发生明显变化,还通过重塑肿瘤浸润T细胞区系抑制了体内ERAP1 KO肿瘤的生长。有趣的是,ERAP1缺失与恩替诺斯他和PD-1阻断联合使用,可克服对PD-1免疫疗法的耐药性,并提高宿主存活率:这些研究结果表明,ERAP1抑制与HDACi恩替诺司他治疗和PD-1阻断相结合,可重塑NB等非免疫原性肿瘤的免疫格局,使其对检查点免疫疗法产生反应。
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引用次数: 0
Correction: TRPM7 promotes the epithelial- mesenchymal transition in ovarian cancer through the calcium-related PI3K / AKT oncogenic signaling. 更正:TRPM7通过与钙相关的PI3K/AKT致癌信号促进卵巢癌的上皮-间质转化。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-21 DOI: 10.1186/s13046-024-03212-7
Lu Liu, Nayiyuan Wu, Ying Wang, Xiaoyun Zhang, Bing Xia, Jie Tang, Jingting Cai, Zitong Zhao, Qianjin Liao, Jing Wang
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引用次数: 0
MCPIP1 modulates the miRNA‒mRNA landscape in keratinocyte carcinomas. MCPIP1 调节角朊细胞癌中 miRNA-mRNA 的分布。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-21 DOI: 10.1186/s13046-024-03211-8
Agata Lichawska-Cieslar, Weronika Szukala, Guillem Ylla, Gabriela Machaj, Faustyna Ploskonka, Iwona Chlebicka, Jacek C Szepietowski, Jolanta Jura

Background: Monocyte Chemotactic Protein 1-Induced Protein 1 (MCPIP1, also called Regnase-1) is a negative modulator of inflammation with tumor-suppressive properties. Mice with keratinocyte-specific deletion of the Zc3h12a gene, encoding MCPIP1, (Mcpip1eKO mice) are more susceptible to the development of epidermal papillomas initiated by 7,12-dimethylbenz[a]-anthracene (DMBA) and promoted by 2-O-tetradecanoylphorbol-13-acetate (TPA).

Methods: The aim of this study was to investigate the MCPIP1 RNase-dependent microRNA (miRNA)‒mRNA regulatory network in chemically induced squamous cell carcinoma (SCC)-like skin papillomas. Next-generation sequencing (NGS) coupled with bioinformatic analysis was used to shortlist the MCPIP1-dependent changes in protein-coding genes and miRNAs. The expression levels of the selected miRNAs were analyzed by quantitative PCR in human keratinocytes with MCPIP1 silencing. Functional studies were performed in human keratinocytes transfected with appropriate miRNA mimics. The DIANA-microT-CDS algorithm and DIANA-TarBase v7 database were used to predict potential target genes and identify the experimentally validated targets of differentially expressed (DE) miRNAs.

Results: RNA sequencing (RNA-Seq) analysis of control and Mcpip1eKO DMBA/TPA-induced papillomas revealed transcriptome changes, with 2400 DE protein-coding genes and 33 DE miRNAs. The expression of miR-223-3p, miR-376c-3p, and miR-139-5p was confirmed to be dependent on MCPIP1 activity in both murine and human models. We showed that MCPIP1 directly regulates the expression of miR-376c-3p via direct cleavage of the corresponding precursor miRNA. The pro-proliferative activity of miR-223-3p, miR-376c-3p, and miR-139-5p was experimentally confirmed in SCC-like keratinocytes. Bioinformatic prediction of the mRNA targets of the DE-miRNAs revealed 416 genes as putative targets of the 18 upregulated miRNAs and 425 genes as putative targets of the 15 downregulated miRNAs. Further analyses revealed the murine interactions that are conserved in humans. Functional analysis indicated that during the development of cutaneous SCC, the most important pathways/processes mediated by the miRNA‒mRNA MCPIP1-dependent network are the regulation of inflammatory processes, epithelial cell proliferation, Wnt signaling, and miRNA transcription.

Conclusions: Loss of MCPIP1 modulates the expression profiles of 33 miRNAs in chemically induced Mcpip1eKO papillomas, and these changes directly affect the miRNA‒mRNA network and the modulation of pathways and processes related to carcinogenesis.

背景:单核细胞趋化蛋白1诱导蛋白1(MCPIP1,又称Regnase-1)是一种具有抑制肿瘤特性的炎症负性调节剂。编码 MCPIP1 的 Zc3h12a 基因的角质细胞特异性缺失小鼠(Mcpip1eKO 小鼠)更容易患上由 7,12-二甲基苯并[a]-蒽(DMBA)引发并由 2-O-十四碳酰樟脑酚-13-乙酸酯(TPA)促进的表皮乳头状瘤:本研究旨在调查化学诱导的鳞状细胞癌(SCC)样皮肤乳头状瘤中依赖于MCPIP1 RNase的微RNA(miRNA)-mRNA调控网络。下一代测序(NGS)与生物信息学分析相结合,筛选出了MCPIP1依赖性蛋白编码基因和miRNA的变化。通过定量 PCR 分析了所选 miRNA 在 MCPIP1 沉默的人类角朊细胞中的表达水平。在转染了适当 miRNA 模拟物的人类角朊细胞中进行了功能研究。利用DIANA-microT-CDS算法和DIANA-TarBase v7数据库预测潜在的靶基因,并确定实验验证的差异表达(DE)miRNAs靶标:结果:对照组和Mcpip1eKO DMBA/TPA诱导的乳头状瘤的RNA测序(RNA-Seq)分析显示了转录组的变化,其中有2400个DE蛋白编码基因和33个DE miRNA。在小鼠和人类模型中,miR-223-3p、miR-376c-3p 和 miR-139-5p 的表达都被证实依赖于 MCPIP1 的活性。我们发现,MCPIP1 通过直接裂解相应的前体 miRNA 直接调节 miR-376c-3p 的表达。实验证实了 miR-223-3p、miR-376c-3p 和 miR-139-5p 在 SCC 样角质形成细胞中的促增殖活性。对 DE-miRNA 的 mRNA 靶点进行生物信息学预测发现,18 个上调的 miRNA 有 416 个基因可能是靶点,15 个下调的 miRNA 有 425 个基因可能是靶点。进一步的分析表明,小鼠的相互作用在人类中是一致的。功能分析表明,在皮肤SCC的发展过程中,由miRNA-mRNA MCPIP1依赖网络介导的最重要通路/过程是炎症过程、上皮细胞增殖、Wnt信号转导和miRNA转录的调控:结论:MCPIP1的缺失会改变化学诱导的Mcpip1eKO乳头状瘤中33种miRNA的表达谱,这些变化直接影响miRNA-mRNA网络以及与癌变相关的通路和过程的调控。
{"title":"MCPIP1 modulates the miRNA‒mRNA landscape in keratinocyte carcinomas.","authors":"Agata Lichawska-Cieslar, Weronika Szukala, Guillem Ylla, Gabriela Machaj, Faustyna Ploskonka, Iwona Chlebicka, Jacek C Szepietowski, Jolanta Jura","doi":"10.1186/s13046-024-03211-8","DOIUrl":"10.1186/s13046-024-03211-8","url":null,"abstract":"<p><strong>Background: </strong>Monocyte Chemotactic Protein 1-Induced Protein 1 (MCPIP1, also called Regnase-1) is a negative modulator of inflammation with tumor-suppressive properties. Mice with keratinocyte-specific deletion of the Zc3h12a gene, encoding MCPIP1, (Mcpip1<sup>eKO</sup> mice) are more susceptible to the development of epidermal papillomas initiated by 7,12-dimethylbenz[a]-anthracene (DMBA) and promoted by 2-O-tetradecanoylphorbol-13-acetate (TPA).</p><p><strong>Methods: </strong>The aim of this study was to investigate the MCPIP1 RNase-dependent microRNA (miRNA)‒mRNA regulatory network in chemically induced squamous cell carcinoma (SCC)-like skin papillomas. Next-generation sequencing (NGS) coupled with bioinformatic analysis was used to shortlist the MCPIP1-dependent changes in protein-coding genes and miRNAs. The expression levels of the selected miRNAs were analyzed by quantitative PCR in human keratinocytes with MCPIP1 silencing. Functional studies were performed in human keratinocytes transfected with appropriate miRNA mimics. The DIANA-microT-CDS algorithm and DIANA-TarBase v7 database were used to predict potential target genes and identify the experimentally validated targets of differentially expressed (DE) miRNAs.</p><p><strong>Results: </strong>RNA sequencing (RNA-Seq) analysis of control and Mcpip1<sup>eKO</sup> DMBA/TPA-induced papillomas revealed transcriptome changes, with 2400 DE protein-coding genes and 33 DE miRNAs. The expression of miR-223-3p, miR-376c-3p, and miR-139-5p was confirmed to be dependent on MCPIP1 activity in both murine and human models. We showed that MCPIP1 directly regulates the expression of miR-376c-3p via direct cleavage of the corresponding precursor miRNA. The pro-proliferative activity of miR-223-3p, miR-376c-3p, and miR-139-5p was experimentally confirmed in SCC-like keratinocytes. Bioinformatic prediction of the mRNA targets of the DE-miRNAs revealed 416 genes as putative targets of the 18 upregulated miRNAs and 425 genes as putative targets of the 15 downregulated miRNAs. Further analyses revealed the murine interactions that are conserved in humans. Functional analysis indicated that during the development of cutaneous SCC, the most important pathways/processes mediated by the miRNA‒mRNA MCPIP1-dependent network are the regulation of inflammatory processes, epithelial cell proliferation, Wnt signaling, and miRNA transcription.</p><p><strong>Conclusions: </strong>Loss of MCPIP1 modulates the expression profiles of 33 miRNAs in chemically induced Mcpip1<sup>eKO</sup> papillomas, and these changes directly affect the miRNA‒mRNA network and the modulation of pathways and processes related to carcinogenesis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479518","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
SEC14L3 knockdown inhibited clear cell renal cell carcinoma proliferation, metastasis and sunitinib resistance through an SEC14L3/RPS3/NFκB positive feedback loop. 通过SEC14L3/RPS3/NFκB正反馈回路,SEC14L3基因敲除抑制了透明细胞肾细胞癌的增殖、转移和舒尼替尼耐药性。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-19 DOI: 10.1186/s13046-024-03206-5
Ziming Jiang, Guangcan Yang, Guangchun Wang, Jiayi Wan, Yifan Zhang, Wei Song, Houliang Zhang, Jinliang Ni, Haipeng Zhang, Ming Luo, Keyi Wang, Bo Peng

Background: Clear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive.

Methods: By leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays.

Results: Our investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth.

Conclusion: Our findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment.

背景:透明细胞肾细胞癌(ccRCC)产生于肾实质上皮,是肾癌中最主要的恶性实体,其发病率和死亡率随着时间的推移不断上升。SEC14-like 3(SEC14L3)已成为癌症干预的一个引人注目的靶点;然而,SEC14L3在ccRCC中的确切临床意义和分子基础仍未确定:方法:通过利用临床数据以及来自 TCGA-ccRCC 和 GEO 数据集的数据,我们研究了 SEC14L3 表达水平与 ccRCC 患者总生存率之间的关系。我们通过体内和体外实验研究了SEC14L3在ccRCC中的生物学作用和机制。此外,还合成了 siRNA-SEC14L3@PDA@MUC12 纳米颗粒(SSPM-NPs),并通过体内和体外实验评估了其对 SEC14L3 的治疗潜力:我们的研究发现,SEC14L3在ccRCC组织中表达上调,外源性下调SEC14L3能有效抑制ccRCC细胞的恶性特征。从机理上讲,敲除 SEC14L3 可促进核糖体蛋白 S3(RPS3)泛素化介导的降解,并增加 IκBα 在 ccRCC 中的积累。这种协同作用阻碍了 P65 的核转位,从而抑制了核因子卡巴 B(NFκB)信号通路的激活,阻碍了 ccRCC 细胞的增殖和转移。此外,SEC14L3水平的降低对NFκB信号级联中NFKB1的表达也有抑制作用。NFKB1 是一种转录调节因子,能与 SEC14L3 增强子和启动子结合,从而促进 SEC14L3 的表达。因此,对 SEC14L3 表达的抑制作用被进一步加强,从而形成了一个正反馈回路。此外,我们还观察到,下调 SEC14L3 能显著提高 ccRCC 细胞对舒尼替尼的敏感性。对SSPM-NPs纳米疗法的评估强调了它与舒尼替尼联合抑制ccRCC生长的有效性:我们的研究结果不仅强调了SEC14L3作为治疗靶点的前景,还揭示了SEC14L3/RPS3/NFκB的正反馈回路,该回路可抑制ccRCC的进展。调节 SEC14L3 的表达以参与这一正反馈环路可能预示着治疗 ccRCC 的新途径。
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引用次数: 0
Noval insights and therapeutic strategies for tumor-induced kidney pathologies. 肿瘤诱发肾脏病变的新观点和治疗策略。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-19 DOI: 10.1186/s13046-024-03205-6
Meng Wang, Yong Han, Chao Zhang

Recent progress in elucidating the role of specific antidiuretic hormones in Drosophila models has provided valuable insights into the mechanisms underlying tumor-induced renal dysfunction. Xu et al. identified the mammalian neurokinin 3 receptor (TACR3), a homolog of the G protein-coupled receptor TkR99D in fruit flies, as a potential therapeutic target for alleviating renal tubular dysfunction in mice with malignant neoplasms. Here, we commented on these findings by emphasizing the structural and evolutionary significance of TACR3 and provided an in-depth analysis of cell type specific expression of TACR3 in response to renal injury and expressional dynamics during renal carcinoma progression. The implications of these findings for transforming the therapeutic approaches to renal complications associated with oncological disorders were highlighted. We also acknowledged the limitations of current experimental models in this study and emphasized the necessary clinical validation in the future. These insights could contribute to the advancement of diagnostic and therapeutic strategies for treating tumor-related renal pathologies.

最近在阐明果蝇模型中特定抗利尿激素的作用方面取得的进展,为了解肿瘤诱发肾功能障碍的机制提供了宝贵的见解。Xu等人发现哺乳动物神经激肽3受体(TACR3)是果蝇中G蛋白偶联受体TkR99D的同源物,是缓解恶性肿瘤小鼠肾小管功能障碍的潜在治疗靶点。在此,我们对这些发现进行了评论,强调了 TACR3 的结构和进化意义,并深入分析了 TACR3 在肾损伤时的细胞特异性表达以及在肾癌进展过程中的表达动态。我们强调了这些发现对改变治疗肿瘤相关肾脏并发症方法的意义。我们也承认本研究中现有实验模型的局限性,并强调了未来必要的临床验证。这些见解将有助于推进治疗肿瘤相关肾脏病变的诊断和治疗策略。
{"title":"Noval insights and therapeutic strategies for tumor-induced kidney pathologies.","authors":"Meng Wang, Yong Han, Chao Zhang","doi":"10.1186/s13046-024-03205-6","DOIUrl":"10.1186/s13046-024-03205-6","url":null,"abstract":"<p><p>Recent progress in elucidating the role of specific antidiuretic hormones in Drosophila models has provided valuable insights into the mechanisms underlying tumor-induced renal dysfunction. Xu et al. identified the mammalian neurokinin 3 receptor (TACR3), a homolog of the G protein-coupled receptor TkR99D in fruit flies, as a potential therapeutic target for alleviating renal tubular dysfunction in mice with malignant neoplasms. Here, we commented on these findings by emphasizing the structural and evolutionary significance of TACR3 and provided an in-depth analysis of cell type specific expression of TACR3 in response to renal injury and expressional dynamics during renal carcinoma progression. The implications of these findings for transforming the therapeutic approaches to renal complications associated with oncological disorders were highlighted. We also acknowledged the limitations of current experimental models in this study and emphasized the necessary clinical validation in the future. These insights could contribute to the advancement of diagnostic and therapeutic strategies for treating tumor-related renal pathologies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479519","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
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Journal of Experimental & Clinical Cancer Research
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