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Synthetic lethality of combined ULK1 defection and p53 restoration induce pyroptosis by directly upregulating GSDME transcription and cleavage activation through ROS/NLRP3 signaling. 结合 ULK1 缺陷和 p53 恢复的合成致死率通过 ROS/NLRP3 信号直接上调 GSDME 的转录和裂解激活,诱导热猝死。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.1186/s13046-024-03168-8
Wei Chen, Kai-Bin Yang, Yuan-Zhe Zhang, Zai-Shan Lin, Jin-Wei Chen, Si-Fan Qi, Chen-Fei Wu, Gong-Kan Feng, Da-Jun Yang, Ming Chen, Xiao-Feng Zhu, Xuan Li

Background: High expression of ubiquitin ligase MDM2 is a primary cause of p53 inactivation in many tumors, making it a promising therapeutic target. However, MDM2 inhibitors have failed in clinical trials due to p53-induced feedback that enhances MDM2 expression. This underscores the urgent need to find an effective adaptive genotype or combination of targets.

Methods: Kinome-wide CRISPR/Cas9 knockout screen was performed to identify genes that modulate the response to MDM2 inhibitor using TP53 wild type cancer cells and found ULK1 as a candidate. The MTT cell viability assay, flow cytometry and LDH assay were conducted to evaluate the activation of pyroptosis and the synthetic lethality effects of combining ULK1 depletion with p53 activation. Dual-luciferase reporter assay and ChIP-qPCR were performed to confirm that p53 directly mediates the transcription of GSDME and to identify the binding region of p53 in the promoter of GSDME. ULK1 knockout / overexpression cells were constructed to investigate the functional role of ULK1 both in vitro and in vivo. The mechanism of ULK1 depletion to activate GSMDE was mainly investigated by qPCR, western blot and ELISA.

Results: By using high-throughput screening, we identified ULK1 as a synthetic lethal gene for the MDM2 inhibitor APG115. It was determined that deletion of ULK1 significantly increased the sensitivity, with cells undergoing typical pyroptosis. Mechanistically, p53 promote pyroptosis initiation by directly mediating GSDME transcription that induce basal-level pyroptosis. Moreover, ULK1 depletion reduces mitophagy, resulting in the accumulation of damaged mitochondria and subsequent increasing of reactive oxygen species (ROS). This in turn cleaves and activates GSDME via the NLRP3-Caspase inflammatory signaling axis. The molecular cascade makes ULK1 act as a crucial regulator of pyroptosis initiation mediated by p53 activation cells. Besides, mitophagy is enhanced in platinum-resistant tumors, and ULK1 depletion/p53 activation has a synergistic lethal effect on these tumors, inducing pyroptosis through GSDME directly.

Conclusion: Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies.

背景:在许多肿瘤中,泛素连接酶 MDM2 的高表达是导致 p53 失活的主要原因,因此它是一个很有前景的治疗靶点。然而,由于 p53 诱导的反馈会增强 MDM2 的表达,MDM2 抑制剂在临床试验中失败了。这凸显了寻找有效的适应性基因型或靶点组合的迫切需要:方法:利用 TP53 野生型癌细胞进行了全基因组 CRISPR/Cas9 基因敲除筛选,以确定可调节对 MDM2 抑制剂反应的基因,结果发现 ULK1 是一个候选基因。研究人员采用 MTT 细胞活力测定法、流式细胞仪和 LDH 分析法评估了 ULK1 基因敲除与 p53 基因激活相结合对热休克的激活和合成致死效应。为了证实 p53 直接介导 GSDME 的转录,并确定 p53 在 GSDME 启动子中的结合区,研究人员进行了双荧光素酶报告实验和 ChIP-qPCR 实验。构建了ULK1敲除/过表达细胞,以研究ULK1在体外和体内的功能作用。主要通过 qPCR、western blot 和 ELISA 等方法研究了 ULK1 缺失激活 GSMDE 的机制:结果:通过高通量筛选,我们发现 ULK1 是 MDM2 抑制剂 APG115 的合成致死基因。结果:通过筛选,我们发现 ULK1 是 MDM2 抑制剂 APG115 的合成致死基因。从机理上讲,p53通过直接介导GSDME转录来诱导基础水平的热休克,从而促进热休克的启动。此外,ULK1 的耗竭会降低有丝分裂,导致受损线粒体的积累和随后活性氧(ROS)的增加。这反过来又会通过 NLRP3-Caspase 炎症信号轴裂解并激活 GSDME。这一分子级联使 ULK1 成为 p53 激活细胞介导的热凋亡启动的关键调节因子。此外,有丝分裂在铂耐药肿瘤中得到增强,ULK1耗竭/p53激活对这些肿瘤具有协同致死效应,直接通过GSDME诱导热噬:p53在激活GSDME转录中起着直接作用,而ULK1的缺乏会引发ROS-NLRP3信号通路的上调,从而导致GSDME的裂解和激活。这些发现强调了 p53 在决定化脓过程中的关键作用,为 p53 恢复疗法的临床应用提供了新的途径,并提出了潜在的组合策略。
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引用次数: 0
Retraction Note: HOXD9 promotes epithelial-mesenchymal transition and cancer metastasis by ZEB1 regulation in hepatocellular carcinoma. 撤稿说明:HOXD9通过调控ZEB1促进肝细胞癌的上皮-间质转化和癌症转移。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.1186/s13046-024-03171-z
Xiupeng Lv, Linlin Li, Li Lv, Xiaotong Qu, Shi Jin, Kejun Li, Xiaoqin Deng, Lei Cheng, Hui He, Lei Dong
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引用次数: 0
CCT3/ACTN4/TFRC axis protects hepatocellular carcinoma cells from ferroptosis by inhibiting iron endocytosis. CCT3/ACTN4/TFRC轴通过抑制铁的内吞保护肝癌细胞免于铁中毒。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-29 DOI: 10.1186/s13046-024-03169-7
Huihui Zhu, Qiuhong Liu, Qinna Meng, Lingjian Zhang, Siwei Ju, Jiaheng Lang, Danhua Zhu, Yongxia Chen, Nadire Aishan, Xiaoxi Ouyang, Sainan Zhang, Lidan Jin, Lanlan Xiao, Linbo Wang, Lanjuan Li, Feiyang Ji

Sorafenib is widely used in treating advanced hepatocellular carcinoma (HCC). However, its effectiveness in prolonging patient survival is limited by the development of drug resistance. To systematically investigate the resistance mechanisms of Sorafenib, an integrative analysis combining posttranslational modification (PTM) omics and CRISPR/Cas9 knockout library screening was conducted. This analysis identified ubiquitination at lysine 21 (K21) on chaperonin-containing TCP1 subunit 3 (CCT3) as being associated with Sorafenib resistance. Transcriptomic data from HCC patients treated with Sorafenib revealed that CCT3 expression was lower in responders compared to non-responders. Experimentally, inhibiting the expression of CCT3 sensitized HCC cells to Sorafenib and enhanced Sorafenib-induced ferroptosis. Additionally, CCT3 was found to interact with ACTN4, hindering the recycling of transferrin receptor protein 1 (TFRC) to the cell membrane, thus obstructing iron endocytosis. Mechanistically, the inhibition of ferroptosis by CCT3 depends on the deubiquitination of K6-linked non-degradative ubiquitination at its K21, which occurs upon Sorafenib treatment. Moreover, CCT3 knockdown enhanced the anti-tumor effects of Sorafenib in nude mice. In summary, we have identified a novel function of the chaperone protein. Targeting the CCT3/ACTN4/TFRC axis offers a promising strategy to enhance ferroptosis and overcome Sorafenib resistance in HCC.

索拉非尼被广泛用于治疗晚期肝细胞癌(HCC)。然而,由于耐药性的产生,它在延长患者生存期方面的有效性受到了限制。为了系统地研究索拉非尼的耐药机制,研究人员结合翻译后修饰(PTM)omics和CRISPR/Cas9基因敲除文库筛选进行了综合分析。该分析确定了含伴侣素的TCP1亚基3(CCT3)上赖氨酸21(K21)处的泛素化与索拉非尼耐药相关。接受索拉非尼治疗的HCC患者的转录组数据显示,与无应答者相比,应答者的CCT3表达量较低。实验表明,抑制 CCT3 的表达可使 HCC 细胞对索拉非尼敏感,并增强索拉非尼诱导的铁变态反应。此外,研究还发现CCT3与ACTN4相互作用,阻碍转铁蛋白受体蛋白1(TFRC)向细胞膜的再循环,从而阻碍铁的内吞。从机理上讲,CCT3对铁的吞吐抑制取决于其K21处与K6相连的非降解泛素化,而这种泛素化在索拉非尼处理后发生。此外,CCT3的敲除增强了索拉非尼对裸鼠的抗肿瘤作用。总之,我们发现了伴侣蛋白的一种新功能。以CCT3/ACTN4/TFRC轴为靶点,为增强铁蛋白沉降和克服HCC对索拉非尼的耐药性提供了一种前景广阔的策略。
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引用次数: 0
Correction: TFEB controls sensitivity to chemotherapy and immuno-killing in non-small cell lung cancer. 更正:TFEB控制着非小细胞肺癌对化疗和免疫杀伤的敏感性。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-29 DOI: 10.1186/s13046-024-03170-0
Muhlis Akman, Ciro Monteleone, Gabriella Doronzo, Martina Godel, Francesca Napoli, Alessandra Merlini, Virginia Campani, Valeria Nele, Elisa Balmas, Tatiana Chontorotzea, Simona Fontana, Sabrina Digiovanni, Francesca Alice Barbu, Elena Astanina, Niloufar Jafari, Iris Chiara Salaroglio, Joanna Kopecka, Giuseppe De Rosa, Thomas Mohr, Alessandro Bertero, Luisella Righi, Silvia Novello, Giorgio Vittorio Scagliotti, Federico Bussolino, Chiara Riganti
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引用次数: 0
Correction: Bispecifc aptamer-decorated and light-triggered nanoparticles targeting tumor and stromal cells in breast cancer derived organoids: implications for precision phototherapies. 更正:以乳腺癌衍生组织细胞中的肿瘤细胞和基质细胞为靶标的双胰蛋白酶适配体装饰和光触发纳米粒子:对精准光疗的启示
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-23 DOI: 10.1186/s13046-024-03159-9
Simona Camorani, Alessandra Caliendo, Elena Morrone, Lisa Agnello, Matteo Martini, Monica Cantile, Margherita Cerrone, Antonella Zannetti, Massimo La Deda, Monica Fedele, Loredana Ricciardi, Laura Cerchia
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引用次数: 0
Circulating cell-free and extracellular vesicles-derived microRNA as prognostic biomarkers in patients with early-stage NSCLC: results from RESTING study. 作为早期 NSCLC 患者预后生物标志物的循环无细胞和细胞外囊泡衍生 microRNA:RESTING 研究的结果。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-22 DOI: 10.1186/s13046-024-03156-y
Elisabetta Petracci, Luigi Pasini, Milena Urbini, Enriqueta Felip, Franco Stella, Fabio Davoli, Maurizio Salvi, Michele Beau-Faller, Michela Tebaldi, Irene Azzali, Matteo Canale, Piergiorgio Solli, Giulia Lai, Ramon Amat, Caterina Carbonell, Pierre-Emmanuel Falcoz, Alex Martinez-Marti, Erwan Pencreach, Angelo Delmonte, Lucio Crinò, Paola Ulivi

Background: Factors to accurately stratify patients with early-stage non-small cell lung cancer (NSCLC) in different prognostic groups are still needed. This study aims to investigate 1) the prognostic potential of circulating cell-free (CF) and extracellular vesicles (EVs)-derived microRNA (miRNAs), and 2) their added value with respect to known prognostic factors (PFs).

Methods: The RESTING study is a multicentre prospective observational cohort study on resected stage IA-IIIA patients with NSCLC. The primary end-point was disease-free survival (DFS), and the main analyses were carried out separately for CF- and EV-miRNAs. CF- and EV-miRNAs were isolated from plasma, and miRNA-specific libraries were prepared and sequenced. To reach the study aims, three statistical models were specified: one using the miRNA data only (Model 1); one using both miRNAs and known PFs (age, gender, and pathological stage) (Model 2), and one using the PFs alone (Model 3). Five-fold cross-validation (CV) was used to assess the predictive performance of each. Standard Cox regression and elastic net regularized Cox regression were used.

Results: A total of 222 patients were enrolled. The median follow-up time was 26.3 (95% CI 25.4-27.6) months. From Model 1, three CF-miRNAs and 21 EV-miRNAs were associated with DFS. In Model 2, two CF-miRNAs (miR-29c-3p and miR-877-3p) and five EV-miRNAs (miR-181a-2-3p, miR-182-5p, miR-192-5p, miR-532-3p and miR-589-5p) remained associated with DFS. From pathway enrichment analysis, TGF-beta and NOTCH were the most involved pathways.

Conclusion: This study identified promising prognostic CF- and EV-miRNAs that could be used as a non-invasive, cost-effective tool to aid clinical decision-making. However, further evaluation of the obtained miRNAs in an external cohort of patients is warranted.

背景:目前仍需要对早期非小细胞肺癌(NSCLC)患者进行准确分层,以确定不同的预后组别。本研究旨在探讨:1)循环无细胞(CF)和细胞外囊泡(EVs)衍生的微RNA(miRNAs)的预后潜力;2)它们相对于已知预后因素(PFs)的附加值:RESTING研究是一项多中心前瞻性观察性队列研究,对象是切除的IA-IIIA期NSCLC患者。主要终点是无病生存期(DFS),主要分析分别针对CF-和EV-miRNA。研究人员从血浆中分离出CF-和EV-miRNA,制备了miRNA特异性文库并进行了测序。为了达到研究目的,我们建立了三个统计模型:一个是仅使用 miRNA 数据的模型(模型 1);一个是同时使用 miRNA 和已知 PFs(年龄、性别和病理分期)的模型(模型 2);一个是仅使用 PFs 的模型(模型 3)。采用五倍交叉验证(CV)来评估每种模型的预测性能。使用了标准 Cox 回归和弹性净正则化 Cox 回归:共有 222 名患者入选。中位随访时间为 26.3(95% CI 25.4-27.6)个月。在模型 1 中,3 个 CF-miRNA 和 21 个 EV-miRNA 与 DFS 相关。在模型2中,2个CF-miRNA(miR-29c-3p和miR-877-3p)和5个EV-miRNA(miR-181a-2-3p、miR-182-5p、miR-192-5p、miR-532-3p和miR-589-5p)仍与DFS相关。从通路富集分析来看,TGF-beta和NOTCH是参与度最高的通路:这项研究发现了有希望的预后CF-和EV-miRNA,它们可作为一种非侵入性、经济有效的工具来帮助临床决策。不过,有必要在外部患者队列中进一步评估所获得的 miRNA。
{"title":"Circulating cell-free and extracellular vesicles-derived microRNA as prognostic biomarkers in patients with early-stage NSCLC: results from RESTING study.","authors":"Elisabetta Petracci, Luigi Pasini, Milena Urbini, Enriqueta Felip, Franco Stella, Fabio Davoli, Maurizio Salvi, Michele Beau-Faller, Michela Tebaldi, Irene Azzali, Matteo Canale, Piergiorgio Solli, Giulia Lai, Ramon Amat, Caterina Carbonell, Pierre-Emmanuel Falcoz, Alex Martinez-Marti, Erwan Pencreach, Angelo Delmonte, Lucio Crinò, Paola Ulivi","doi":"10.1186/s13046-024-03156-y","DOIUrl":"10.1186/s13046-024-03156-y","url":null,"abstract":"<p><strong>Background: </strong>Factors to accurately stratify patients with early-stage non-small cell lung cancer (NSCLC) in different prognostic groups are still needed. This study aims to investigate 1) the prognostic potential of circulating cell-free (CF) and extracellular vesicles (EVs)-derived microRNA (miRNAs), and 2) their added value with respect to known prognostic factors (PFs).</p><p><strong>Methods: </strong>The RESTING study is a multicentre prospective observational cohort study on resected stage IA-IIIA patients with NSCLC. The primary end-point was disease-free survival (DFS), and the main analyses were carried out separately for CF- and EV-miRNAs. CF- and EV-miRNAs were isolated from plasma, and miRNA-specific libraries were prepared and sequenced. To reach the study aims, three statistical models were specified: one using the miRNA data only (Model 1); one using both miRNAs and known PFs (age, gender, and pathological stage) (Model 2), and one using the PFs alone (Model 3). Five-fold cross-validation (CV) was used to assess the predictive performance of each. Standard Cox regression and elastic net regularized Cox regression were used.</p><p><strong>Results: </strong>A total of 222 patients were enrolled. The median follow-up time was 26.3 (95% CI 25.4-27.6) months. From Model 1, three CF-miRNAs and 21 EV-miRNAs were associated with DFS. In Model 2, two CF-miRNAs (miR-29c-3p and miR-877-3p) and five EV-miRNAs (miR-181a-2-3p, miR-182-5p, miR-192-5p, miR-532-3p and miR-589-5p) remained associated with DFS. From pathway enrichment analysis, TGF-beta and NOTCH were the most involved pathways.</p><p><strong>Conclusion: </strong>This study identified promising prognostic CF- and EV-miRNAs that could be used as a non-invasive, cost-effective tool to aid clinical decision-making. However, further evaluation of the obtained miRNAs in an external cohort of patients is warranted.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019442","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
Molecular understanding and clinical aspects of tumor-associated macrophages in the immunotherapy of renal cell carcinoma. 肿瘤相关巨噬细胞在肾细胞癌免疫疗法中的分子认识和临床应用。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-22 DOI: 10.1186/s13046-024-03164-y
Han Liu, Zongwei Lv, Gong Zhang, Zhenhong Yan, Song Bai, Dan Dong, Kefeng Wang

Renal cell carcinoma (RCC) is one of the most common tumors that afflicts the urinary system, accounting for 90-95% of kidney cancer cases. Although its incidence has increased over the past decades, its pathogenesis is still unclear. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising more than 50% of the tumor volume. By interacting with cancer cells, TAMs can be polarized into two distinct phenotypes, M1-type and M2-type TAMs. In the TME, M2-type TAMs, which are known to promote tumorigenesis, are more abundant than M1-type TAMs, which are known to suppress tumor growth. This ratio of M1 to M2 TAMs can create an immunosuppressive environment that contributes to tumor cell progression and survival. This review focused on the role of TAMs in RCC, including their polarization, impacts on tumor proliferation, angiogenesis, invasion, migration, drug resistance, and immunosuppression. In addition, we discussed the potential of targeting TAMs for clinical therapy in RCC. A deeper understanding of the molecular biology of TAMs is essential for exploring innovative therapeutic strategies for the treatment of RCC.

肾细胞癌(RCC)是泌尿系统最常见的肿瘤之一,占肾癌病例的 90-95%。尽管过去几十年来其发病率有所上升,但其发病机制仍不清楚。肿瘤相关巨噬细胞(TAMs)是肿瘤微环境(TME)中最主要的免疫细胞,占肿瘤体积的 50%以上。通过与癌细胞相互作用,TAMs 可极化为两种不同的表型,即 M1 型和 M2 型 TAMs。在TME中,已知促进肿瘤发生的M2型TAMs比已知抑制肿瘤生长的M1型TAMs更多。M1 型 TAM 与 M2 型 TAM 的这种比例可创造一种免疫抑制环境,从而促进肿瘤细胞的进展和存活。本综述重点探讨了 TAMs 在 RCC 中的作用,包括其极化、对肿瘤增殖、血管生成、侵袭、迁移、耐药性和免疫抑制的影响。此外,我们还讨论了靶向 TAMs 在 RCC 临床治疗中的潜力。加深对TAMs分子生物学的了解对于探索治疗RCC的创新疗法至关重要。
{"title":"Molecular understanding and clinical aspects of tumor-associated macrophages in the immunotherapy of renal cell carcinoma.","authors":"Han Liu, Zongwei Lv, Gong Zhang, Zhenhong Yan, Song Bai, Dan Dong, Kefeng Wang","doi":"10.1186/s13046-024-03164-y","DOIUrl":"10.1186/s13046-024-03164-y","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) is one of the most common tumors that afflicts the urinary system, accounting for 90-95% of kidney cancer cases. Although its incidence has increased over the past decades, its pathogenesis is still unclear. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising more than 50% of the tumor volume. By interacting with cancer cells, TAMs can be polarized into two distinct phenotypes, M1-type and M2-type TAMs. In the TME, M2-type TAMs, which are known to promote tumorigenesis, are more abundant than M1-type TAMs, which are known to suppress tumor growth. This ratio of M1 to M2 TAMs can create an immunosuppressive environment that contributes to tumor cell progression and survival. This review focused on the role of TAMs in RCC, including their polarization, impacts on tumor proliferation, angiogenesis, invasion, migration, drug resistance, and immunosuppression. In addition, we discussed the potential of targeting TAMs for clinical therapy in RCC. A deeper understanding of the molecular biology of TAMs is essential for exploring innovative therapeutic strategies for the treatment of RCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019404","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
Connecting the dots: investigating the link between environmental, genetic, and epigenetic influences in metabolomic alterations in oral squamous cell carcinoma. 连接点:研究口腔鳞状细胞癌代谢组学改变中环境、遗传和表观遗传影响之间的联系。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-21 DOI: 10.1186/s13046-024-03141-5
Ishita Gupta, Fariba Badrzadeh, Yuri Tsentalovich, Daria A Gaykalova

Oral squamous cell carcinoma (OSCC) accounts for around 90% of all oral cancers and is the eighth most common cancer worldwide. Despite progress in managing OSCC, the overall prognosis remains poor, with a survival rate of around 50-60%, largely due to tumor size and recurrence. The challenges of late-stage diagnosis and limitations in current methods emphasize the urgent need for less invasive techniques to enable early detection and treatment, crucial for improving outcomes in this aggressive form of oral cancer. Research is currently aimed at unraveling tumor-specific metabolite profiles to identify candidate biomarkers as well as discover underlying pathways involved in the onset and progression of cancer that could be used as new targets for diagnostic and therapeutic purposes. Metabolomics is an advanced technological approach to identify metabolites in different sample types (biological fluids and tissues). Since OSCC promotes metabolic reprogramming influenced by a combination of genetic predisposition and environmental factors, including tobacco and alcohol consumption, and viral infections, the identification of distinct metabolites through screening may aid in the diagnosis of this condition. Moreover, studies have shown the use of metabolites during the catalysis of epigenetic modification, indicating a link between epigenetics and metabolism. In this review, we will focus on the link between environmental, genetic, and epigenetic influences in metabolomic alterations in OSCC. In addition, we will discuss therapeutic targets of tumor metabolism, which may prevent oral tumor growth, metastasis, and drug resistance.

口腔鳞状细胞癌(OSCC)约占所有口腔癌的 90%,是全球第八大常见癌症。尽管在治疗 OSCC 方面取得了进展,但总体预后仍然很差,生存率约为 50-60%,这主要是由于肿瘤大小和复发造成的。晚期诊断所面临的挑战和现有方法的局限性强调了对微创技术的迫切需求,以实现早期检测和治疗,这对改善这种侵袭性口腔癌的治疗效果至关重要。目前的研究旨在揭示肿瘤特异性代谢物谱,以确定候选生物标志物,并发现癌症发生和发展的潜在途径,这些途径可作为诊断和治疗的新目标。代谢组学是一种先进的技术方法,用于鉴定不同样本类型(生物液体和组织)中的代谢物。由于 OSCC 受遗传易感性和环境因素(包括吸烟、饮酒和病毒感染)的共同影响,会促进代谢重编程,因此通过筛查鉴定不同的代谢物可能有助于诊断这种疾病。此外,研究表明,代谢物在催化表观遗传学修饰过程中的使用,表明了表观遗传学与新陈代谢之间的联系。在本综述中,我们将重点讨论 OSCC 代谢组学改变中环境、遗传和表观遗传影响之间的联系。此外,我们还将讨论肿瘤代谢的治疗靶点,这些靶点可防止口腔肿瘤的生长、转移和耐药性。
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引用次数: 0
The DNA repair pathway as a therapeutic target to synergize with trastuzumab deruxtecan in HER2-targeted antibody-drug conjugate-resistant HER2-overexpressing breast cancer. 将DNA修复途径作为治疗靶点,与曲妥珠单抗德鲁司坦协同治疗HER2靶向抗体-药物共轭物耐药的HER2表达缺失乳腺癌。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-21 DOI: 10.1186/s13046-024-03143-3
Jangsoon Lee, Kumiko Kida, Jiwon Koh, Huey Liu, Ganiraju C Manyam, Young Jin Gi, Dileep R Rampa, Asha S Multani, Jing Wang, Gitanjali Jayachandran, Dae-Won Lee, James M Reuben, Aysegul Sahin, Lei Huo, Debu Tripathy, Seock-Ah Im, Naoto T Ueno

Background: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo.

Methods: Targeted DNA and whole transcriptome sequencing were performed in breast cancer patient tissue samples to investigate genetic aberrations that arose after anti-HER2 therapy. We generated T-DM1 and T-DXd-resistant HER2+ breast cancer cell lines. To elucidate their resistance mechanisms and to identify potential synergistic kinase targets for enhancing the efficacy of T-DXd, we used fluorescence in situ hybridization, droplet digital PCR, Western blotting, whole-genome sequencing, cDNA microarray, and synthetic lethal kinome RNA interference screening. In addition, cell viability, colony formation, and xenograft assays were used to determine the synergistic antitumor effect of T-DXd combinations.

Results: We found reduced HER2 expression in patients and amplified DNA repair-related genes in patients after anti-HER2 therapy. Reduced ERBB2 gene amplification in HER2-directed ADC-resistant HER2+ breast cancer cell lines was through DNA damage and epigenetic mechanisms. In HER2-directed ADC-resistant HER2+ breast cancer cell lines, our non-biased RNA interference screening identified the DNA repair pathway as a potential target within the canonical pathways to enhance the efficacy of T-DXd. We validated that the combination of T-DXd with ataxia telangiectasia and Rad3-related inhibitor, elimusertib, led to significant breast cancer cell death in vitro (P < 0.01) and in vivo (P < 0.01) compared to single agents.

Conclusions: The DNA repair pathways contribute to HER2-directed ADC resistance. Our data justify exploring the combination treatment of T-DXd with DNA repair-targeting drugs to treat HER2-directed ADC-resistant HER2+ breast cancer in clinical trials.

背景:抗HER2疗法,包括HER2抗体-药物共轭物(ADCs)曲妥珠单抗埃坦新(T-DM1)和曲妥珠单抗德鲁司坦(T-DXd),已经改善了HER2表达(HER2+)转移性乳腺癌患者的生存状况。然而,这些患者对基于抗HER2的疗法的内在或获得性耐药性仍然是一项临床挑战,因为疾病进展后没有标准的治疗方法。本研究的目的是阐明HER2+ BC患者和临床前模型对T-DM1和T-DXd的耐药机制,并确定抑制T-DXd可增强体外和体内HER2定向ADC耐药HER2+乳腺癌抗肿瘤活性的靶点:方法:我们对乳腺癌患者组织样本进行了靶向 DNA 和全转录组测序,以研究抗 HER2 治疗后出现的基因畸变。我们生成了 T-DM1 和 T-DXd 抗性 HER2+ 乳腺癌细胞系。为了阐明它们的耐药机制并确定潜在的协同激酶靶点以提高 T-DXd 的疗效,我们使用了荧光原位杂交、液滴数字 PCR、Western 印迹、全基因组测序、cDNA 微阵列和合成致死激酶组 RNA 干扰筛选。此外,我们还使用了细胞活力、集落形成和异种移植试验来确定T-DXd组合的协同抗肿瘤效应:结果:我们发现经过抗HER2治疗后,患者体内的HER2表达减少,DNA修复相关基因扩增。在HER2定向ADC耐药的HER2+乳腺癌细胞系中,ERBB2基因扩增的减少是通过DNA损伤和表观遗传机制实现的。在HER2定向ADC耐药的HER2+乳腺癌细胞系中,我们的非偏倚RNA干扰筛选确定了DNA修复途径是增强T-DXd疗效的典型途径中的一个潜在靶点。我们验证了T-DXd与共济失调毛细血管扩张症和Rad3相关抑制剂elimusertib联合使用可导致体外乳腺癌细胞显著死亡(P结论):DNA修复途径导致了HER2导向的ADC耐药性。我们的数据证明了在临床试验中探索 T-DXd 与 DNA 修复靶向药物联合治疗 HER2 定向 ADC 耐药的 HER2+ 乳腺癌是合理的。
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引用次数: 0
Circulating tumour DNA dynamics predict recurrence in stage III melanoma patients receiving neoadjuvant immunotherapy. 循环肿瘤 DNA 动态预测接受新辅助免疫疗法的 III 期黑色素瘤患者的复发。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-08-21 DOI: 10.1186/s13046-024-03153-1
Wei Yen Chan, Jenny H Lee, Ashleigh Stewart, Russell J Diefenbach, Maria Gonzalez, Alexander M Menzies, Christian Blank, Richard A Scolyer, Georgina V Long, Helen Rizos

Background: Neoadjuvant therapy improves recurrence-free survival (RFS) in resectable stage III cutaneous melanoma. However, accurately predicting individual recurrence risk remains a significant challenge. We investigated circulating tumour DNA (ctDNA) as a biomarker for recurrence in measurable stage IIIB/C melanoma patients undergoing neoadjuvant immunotherapy.

Methods: Plasma samples were collected pre-neoadjuvant treatment, pre-surgery and/or six weeks post-surgery from 40 patients enrolled in the OpACIN-neo and PRADO clinical trials. Patients received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent unbiased pre-amplification followed by tumour-informed mutation detection using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system.

Results: Pre-treatment ctDNA was detectable in 19/40 (48%) patients. Among these, 17/19 (89%) zero-converted within six weeks of surgery and none recurred. Positive ctDNA post-surgery (N = 4), irrespective of pre-treatment ctDNA status, was 100% predictive of recurrence (sensitivity 44%, specificity 100%). Furthermore, ctDNA cleared prior to surgery in 7/9 (78%) patients who did not recur, warranting further investigation into ctDNA-guided surgical management.

Conclusion: Post-surgery ctDNA positivity and zero-conversion are highly predictive of recurrence, offering a window for personalised modification of adjuvant therapy.

背景:新辅助治疗可提高可切除III期皮肤黑色素瘤患者的无复发生存率(RFS)。然而,准确预测个体复发风险仍是一项重大挑战。我们将循环肿瘤DNA(ctDNA)作为接受新辅助免疫疗法的可测量IIIB/C期黑色素瘤患者复发的生物标志物进行了研究:方法:对参加OpACIN-neo和PRADO临床试验的40名患者进行新辅助治疗前、手术前和/或手术后六周的血浆样本采集。患者在手术前接受两个周期的ipilimumab(抗CTLA-4)和nivolumab(抗PD-1)治疗。细胞游离DNA(cfDNA)经过无偏预扩增,然后使用Bio-Rad QX600 PCR系统的液滴数字聚合酶链反应(ddPCR)进行肿瘤信息突变检测:19/40(48%)名患者在治疗前可检测到ctDNA。其中,17/19(89%)例患者在手术后六周内零转化,无一例复发。无论治疗前ctDNA状态如何,手术后ctDNA阳性(N = 4)100%可预测复发(敏感性44%,特异性100%)。此外,7/9(78%)名未复发患者的ctDNA在手术前已清除,因此有必要进一步研究ctDNA指导下的手术治疗:结论:手术后ctDNA阳性和零转换高度预测复发,为辅助治疗的个性化调整提供了窗口。
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Journal of Experimental & Clinical Cancer Research
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