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Co-occurring mutations identify prognostic subgroups of microsatellite stable colorectal cancer 共存突变确定微卫星稳定型结直肠癌的预后亚组
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-25 DOI: 10.1186/s12943-024-02173-x
Luís Nunes, Jakob Mørkved Stenersen, Kushtrim Kryeziu, Tobias Sjöblom, Bengt Glimelius, Ragnhild A. Lothe, Anita Sveen
Co-occurring mutations in pairs of genes can pinpoint clinically relevant subgroups of cancer. Most colorectal cancers (CRCs) are microsatellite stable (MSS) and have few frequent mutations. Large patient cohorts and broad genomic coverage are needed for comprehensive co-mutation profiling. Co-mutations were identified in a population-based Swedish cohort analyzed by whole-genome sequencing (n=819 stage I-IV MSS CRCs). Prognostic value was further evaluated in a publicly available dataset of clinically sequenced metastatic CRCs (MSK-IMPACT; n=934 MSS). Multivariable Cox proportional hazards analyses with clinicopathological parameters were performed for locoregional (stage I-III) and metastatic (stage IV and recurrent) cancers separately. Prevalent co-mutations were detected in 23 unique gene pairs, 20 of which included APC, TP53, KRAS and/or PIK3CA. Several co-mutations involving APC were associated with good overall survival in locoregional CRC, including APC-TCF7L2 (multivariable HR: 0.49, 95% CI 0.27-0.89). This co-mutation was prognostic also in metastatic cancers (multivariable HR: 0.49 and 0.37, 95% CI: 0.24-0.98 and 0.17-0.82 in the Swedish and MSK cohorts, respectively). APC-SOX9 co-mutations were mutually exclusive with APC-TCF7L2, and the co-mutations combined had stronger prognostic associations than APC alone in both metastatic cohorts. BRAF p.V600E-RNF43 co-mutations were associated with poor overall and recurrence-free survival in locoregional CRC (multivariable HR: 4.13 and 3.2, 95% CI: 1.78-9.54 and 1.53-8.04, respectively). We report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone.
成对基因中同时出现的突变可以确定与临床相关的癌症亚群。大多数结直肠癌(CRC)都是微卫星稳定癌(MSS),很少有频繁的突变。要进行全面的共突变分析,需要庞大的患者队列和广泛的基因组覆盖。通过全基因组测序分析(819 例 I-IV 期 MSS 型 CRC),在基于人群的瑞典队列中发现了共突变。临床测序转移性 CRC 的公开数据集(MSK-IMPACT;n=934 MSS)进一步评估了预后价值。对局部癌症(I-III期)和转移性癌症(IV期和复发性)分别进行了临床病理参数的多变量Cox比例危险度分析。在 23 个独特的基因对中检测到了普遍的共突变,其中 20 个基因对包括 APC、TP53、KRAS 和/或 PIK3CA。涉及 APC 的几个共突变与局部 CRC 的良好总生存率相关,包括 APC-TCF7L2(多变量 HR:0.49,95% CI 0.27-0.89)。这种共突变也是转移性癌症的预后因素(瑞典和 MSK 队列中的多变量 HR 分别为 0.49 和 0.37,95% CI 分别为 0.24-0.98 和 0.17-0.82)。APC-SOX9共突变与APC-TCF7L2互斥,在两个转移性队列中,共突变的组合比单独的APC具有更强的预后相关性。在局部 CRC 中,BRAF p.V600E-RNF43 共突变与总生存期和无复发生存期差相关(多变量 HR:4.13 和 3.2,95% CI:1.78-9.54 和 1.53-8.04)。我们报告了对MSS CRC中共生突变的全基因组评估,并认为与单个突变相比,共生突变可改善预后分层。
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引用次数: 0
Single-cell RNA sequencing reveals immune microenvironment niche transitions during the invasive and metastatic processes of ground-glass nodules and part-solid nodules in lung adenocarcinoma 单细胞 RNA 测序揭示肺腺癌磨玻璃结节和部分实性结节侵袭和转移过程中的免疫微环境生态位转换
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-23 DOI: 10.1186/s12943-024-02177-7
Yi-Feng Ren, Qiong Ma, Xiao Zeng, Chun-Xia Huang, Jia-Li Ren, Fang Li, Jia-Jing Tong, Jia-Wei He, Yang Zhong, Shi-Yan Tan, Hua Jiang, Long-Fei Zhang, Heng-Zhou Lai, Ping Xiao, Xiang Zhuang, Peng Wu, Li-Ting You, Wei Shi, Xi Fu, Chuan Zheng, Feng-Ming You
Radiographically, ground-glass nodules (GGN) and part-solid nodules (PSN) in lung adenocarcinoma (LUAD) have significant heterogeneity in their clinical manifestations, biological characteristics, and prognosis. This study aimed to explore the heterogeneity of LUAD in different radiological phenotypes and associated factors influencing tumor evolution. We performed single-cell RNA sequencing (scRNA-seq) on tumor tissues from eight and seven cases of GGN– and PSN–LUAD, respectively, at different disease stages, including minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma (IAC), and metastatic lung cancer (MLC). Additionally, we analyzed adjacent normal tissues from four cases. Immunohistochemistry, multiplex immunofluorescence, and external scRNA-seq data were employed to confirm the expression of signature genes as well as the distribution patterns of CXCL9 + TAMs and TREM2 + TAMs. A LUAD mouse model was generated using gene editing, organoid culture, and orthotopic transplantation techniques, and comprehensive analyses such as histopathology, RNA sequencing, and Western blotting were performed to validate key pathways. Diverse cellular compositions were observed in the tumor microenvironment (TME) during GGN– and PSN–LUAD invasion and metastasis. Notably, CXCL9 + and TREM2 + tumor-associated macrophages (TAMs) exhibited the most significant enrichment changes. It was found that GGN–LUAD exhibited a stronger immune response than PSN–LUAD, with increased interaction between CXCL9 + TAMs and CD8 + tissue-resident memory T cells during invasion stage (MIA–IAC). Conversely, greater interactions between TREM2 + TAMs and tumor cells were observed in PSN–LUAD during the MLC stage. Additionally, TREM2 + TAMs were found to differentiate into TREM2 + /SPP1 + and TREM2 + /SPP1– TAMs at different stages, which promotes tumor progression. This study also emphasizes that during the transdifferentiation process of GGN– and PSN–LUAD, IFN-γ activates the STAT1 signaling pathway to regulate the activation of CXCL9 + TAMs, and further recruiting CD8 + Trm cells and activating T cells through MHC class I antigen presentation. The role of the IFN-γ/STAT1 pathway in the occurrence and development of LUAD was further validated by animal experiments. Our findings offer a potential therapeutic strategy to maintain a dynamic balance within the TME and improve the immunotherapy efficacy by modulating the relative proportions and functional states of CXCL9 + TAMs and TREM2 + TAMs.
从影像学角度看,肺腺癌(LUAD)中的磨玻璃结节(GGN)和部分实性结节(PSN)在临床表现、生物学特征和预后方面具有显著的异质性。本研究旨在探讨肺腺癌不同放射学表型的异质性以及影响肿瘤演变的相关因素。我们分别对 8 例 GGN 型和 7 例 PSN 型 LUAD 的肿瘤组织进行了单细胞 RNA 测序(scRNA-seq),这些肿瘤组织处于不同的疾病分期,包括微侵袭性腺癌(MIA)、侵袭性腺癌(IAC)和转移性肺癌(MLC)。此外,我们还分析了四个病例的邻近正常组织。我们采用免疫组化、多重免疫荧光和外部 scRNA-seq 数据来确认特征基因的表达以及 CXCL9 + TAMs 和 TREM2 + TAMs 的分布模式。利用基因编辑、类器官培养和正位移植技术生成了LUAD小鼠模型,并进行了组织病理学、RNA测序和Western印迹等综合分析,以验证关键通路。在GGN和PSN-LUAD的侵袭和转移过程中,肿瘤微环境(TME)中观察到了不同的细胞组成。值得注意的是,CXCL9 + 和 TREM2 + 肿瘤相关巨噬细胞(TAMs)表现出最显著的富集变化。研究发现,GGN-LUAD 比 PSN-LUAD 表现出更强的免疫反应,在侵袭阶段(MIA-IAC),CXCL9 + TAMs 与 CD8 + 组织驻留记忆 T 细胞之间的相互作用增加。相反,PSN-LUAD 在 MLC 阶段观察到 TREM2 + TAMs 与肿瘤细胞之间有更多的相互作用。此外,研究还发现 TREM2 + TAMs 在不同阶段会分化成 TREM2 + /SPP1 + 和 TREM2 + /SPP1- TAMs,从而促进肿瘤的进展。该研究还强调,在GGN-和PSN-LUAD的转分化过程中,IFN-γ激活STAT1信号通路,调控CXCL9 + TAMs的活化,并进一步招募CD8 + Trm细胞,通过MHC I类抗原呈递激活T细胞。动物实验进一步验证了 IFN-γ/STAT1 通路在 LUAD 发生和发展中的作用。我们的研究结果提供了一种潜在的治疗策略,即通过调节 CXCL9 + TAMs 和 TREM2 + TAMs 的相对比例和功能状态来维持 TME 内的动态平衡并提高免疫疗法的疗效。
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引用次数: 0
Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer 原发性和转移性乳腺癌的代谢重编程和治疗耐药性
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-21 DOI: 10.1186/s12943-024-02165-x
Shan Liu, Xingda Zhang, Wenzheng Wang, Xue Li, Xue Sun, Yuqian Zhao, Qi Wang, Yingpu Li, Fangjie Hu, He Ren
Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt to their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth and contributes to treatment resistance. In primary breast cancer, metabolic shifts such as the Warburg effect and enhanced lipid synthesis are closely linked to chemotherapy failure. Similarly, metastatic lesions often display distinct metabolic profiles that not only sustain tumor growth but also confer resistance to targeted therapies and immunotherapies. The review emphasizes two major aspects: the mechanisms driving metabolic resistance in both primary and metastatic breast cancer, and how the unique metabolic environments in metastatic sites further complicate treatment. By targeting distinct metabolic vulnerabilities at both the primary and metastatic stages, new strategies could improve the efficacy of existing therapies and provide better outcomes for breast cancer patients.
代谢改变是癌症的标志之一,它使肿瘤细胞能够通过调节葡萄糖、脂质和氨基酸代谢来适应环境,从而促进肿瘤细胞快速生长并产生抗药性。在原发性乳腺癌中,沃伯格效应和脂质合成增强等代谢转变与化疗失败密切相关。同样,转移性病灶往往显示出独特的代谢特征,不仅能维持肿瘤生长,还能产生对靶向疗法和免疫疗法的抗药性。综述强调了两个主要方面:原发性和转移性乳腺癌代谢耐药性的驱动机制,以及转移部位独特的代谢环境如何使治疗更加复杂。通过针对原发性和转移性阶段不同的代谢弱点,新策略可以提高现有疗法的疗效,为乳腺癌患者提供更好的治疗结果。
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引用次数: 0
Myofibroblast-derived extracellular vesicles facilitate cancer stemness of hepatocellular carcinoma via transferring ITGA5 to tumor cells 来源于肌成纤维细胞的细胞外囊泡通过向肿瘤细胞转移 ITGA5 促进肝细胞癌的癌症干细胞化
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-21 DOI: 10.1186/s12943-024-02170-0
Yang Xiao, Ping Tao, Keke Zhang, Liuyan Chen, Jinyu Lv, Zhiwei Chen, Lu He, Hongling Jia, Jian Sun, Mingrong Cao, Jian Hong, Chen Qu
Myofibroblasts constitute a significant component of the tumor microenvironment (TME) and play a pivotal role in the progression of hepatocellular carcinoma (HCC). Integrin α5 (ITGA5) is a crucial regulator in myofibroblasts of malignant tumors. Therefore, the potential of ITGA5 as a novel target for the therapeutic strategy of HCC should be investigated. Digital scanning and analysis of the HCC tissue microarray were performed to locate the distribution of ITGA5 and conduct the prognosis analysis. CRISPR Cas9-mediated ITGA5 knockout was performed to establish the ITGA5-KO myofibroblast cell line. Extracellular vesicles (EVs) derived from LX2 were extracted for the treatment of HCC cells. Subsequently, the sphere-forming ability and the stemness markers expression of the treated HCC cells were examined. An orthotopic HCC mouse model with fibrotic injury was constructed to test the outcomes of ITGA5-targeting therapy and its efficacy in the programmed death-ligand 1 (PD-L1) treatment. Co-immunoprecipitation/mass spectrometry and transcriptome data were integrated to delve into the mechanism. The tissue microarray results revealed that ITGA5 was highly enriched in the stromal myofibroblasts of HCC tissues and contributed to enhanced tumor progression and poor prognosis. Notably, ITGA5 transmission via extracellular vesicles (EVs) from myofibroblasts to HCC cells induced the acquisition of cancer stem cell-like properties. Mechanistically, ITGA5 directly bind to YES1, facilitating the activation of YES1 and its downstream pathways, thereby enhancing the stemness of HCC cells. Furthermore, the blockade of ITGA5 impeded tumor progression driven by ITGA5+ myofibroblasts and enhanced the efficacy of treatment with PD-L1 in a mouse model of HCC. Our findings elucidated a novel mechanism by which the EV-mediated transfer of ITGA5 from myofibroblasts to tumor cells augmented HCC stemness. ITGA5-targeting therapy helped prevent the progression of HCC and improved the efficacy of PD-L1 treatment.
肌成纤维细胞是肿瘤微环境(TME)的重要组成部分,在肝细胞癌(HCC)的发展过程中起着关键作用。整合素α5(ITGA5)是恶性肿瘤肌成纤维细胞的重要调节因子。因此,应研究 ITGA5 作为 HCC 治疗策略新靶点的潜力。研究人员对HCC组织芯片进行了数字扫描和分析,以确定ITGA5的分布并进行预后分析。通过CRISPR Cas9介导的ITGA5基因敲除,建立了ITGA5-KO肌成纤维细胞系。提取来自LX2的胞外小泡(EVs)处理HCC细胞。随后,研究人员检测了处理后的 HCC 细胞的成球能力和干性标志物的表达。为了检测ITGA5靶向治疗的结果及其在程序性死亡配体1(PD-L1)治疗中的疗效,研究人员构建了带有纤维化损伤的HCC小鼠模型。研究人员整合了免疫沉淀/质谱和转录组数据,以深入研究其机制。组织芯片研究结果显示,ITGA5高度富集于HCC组织的基质肌成纤维细胞中,并导致肿瘤恶化和预后不良。值得注意的是,ITGA5通过胞外囊泡(EVs)从肌成纤维细胞传递到HCC细胞,诱导了肿瘤干细胞样特性的获得。从机制上讲,ITGA5直接与YES1结合,促进了YES1及其下游通路的激活,从而增强了HCC细胞的干性。此外,在小鼠HCC模型中,阻断ITGA5可阻碍由ITGA5+肌成纤维细胞驱动的肿瘤进展,并增强PD-L1治疗的疗效。我们的研究结果阐明了一种新的机制,即由EV介导的ITGA5从肌成纤维细胞转移到肿瘤细胞可增强HCC干性。ITGA5靶向疗法有助于防止HCC的恶化,并提高了PD-L1治疗的疗效。
{"title":"Myofibroblast-derived extracellular vesicles facilitate cancer stemness of hepatocellular carcinoma via transferring ITGA5 to tumor cells","authors":"Yang Xiao, Ping Tao, Keke Zhang, Liuyan Chen, Jinyu Lv, Zhiwei Chen, Lu He, Hongling Jia, Jian Sun, Mingrong Cao, Jian Hong, Chen Qu","doi":"10.1186/s12943-024-02170-0","DOIUrl":"https://doi.org/10.1186/s12943-024-02170-0","url":null,"abstract":"Myofibroblasts constitute a significant component of the tumor microenvironment (TME) and play a pivotal role in the progression of hepatocellular carcinoma (HCC). Integrin α5 (ITGA5) is a crucial regulator in myofibroblasts of malignant tumors. Therefore, the potential of ITGA5 as a novel target for the therapeutic strategy of HCC should be investigated. Digital scanning and analysis of the HCC tissue microarray were performed to locate the distribution of ITGA5 and conduct the prognosis analysis. CRISPR Cas9-mediated ITGA5 knockout was performed to establish the ITGA5-KO myofibroblast cell line. Extracellular vesicles (EVs) derived from LX2 were extracted for the treatment of HCC cells. Subsequently, the sphere-forming ability and the stemness markers expression of the treated HCC cells were examined. An orthotopic HCC mouse model with fibrotic injury was constructed to test the outcomes of ITGA5-targeting therapy and its efficacy in the programmed death-ligand 1 (PD-L1) treatment. Co-immunoprecipitation/mass spectrometry and transcriptome data were integrated to delve into the mechanism. The tissue microarray results revealed that ITGA5 was highly enriched in the stromal myofibroblasts of HCC tissues and contributed to enhanced tumor progression and poor prognosis. Notably, ITGA5 transmission via extracellular vesicles (EVs) from myofibroblasts to HCC cells induced the acquisition of cancer stem cell-like properties. Mechanistically, ITGA5 directly bind to YES1, facilitating the activation of YES1 and its downstream pathways, thereby enhancing the stemness of HCC cells. Furthermore, the blockade of ITGA5 impeded tumor progression driven by ITGA5+ myofibroblasts and enhanced the efficacy of treatment with PD-L1 in a mouse model of HCC. Our findings elucidated a novel mechanism by which the EV-mediated transfer of ITGA5 from myofibroblasts to tumor cells augmented HCC stemness. ITGA5-targeting therapy helped prevent the progression of HCC and improved the efficacy of PD-L1 treatment. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"73 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells 靶向线粒体:恢复衰竭 T 细胞的抗肿瘤功效
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1186/s12943-024-02175-9
Mei-Qi Yang, Shu-Ling Zhang, Li Sun, Le-Tian Huang, Jing Yu, Jie-Hui Zhang, Yuan Tian, Cheng-Bo Han, Jie-Tao Ma
Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.
免疫检查点阻断疗法为癌症治疗带来了革命性的变化,但抗药性仍然普遍存在,其原因往往是肿瘤浸润淋巴细胞功能失调。造成这种功能障碍的一个关键因素是线粒体功能障碍,其特点是氧化磷酸化缺陷、适应性受损和去极化,这会促进T细胞衰竭并严重影响抗肿瘤疗效。本综述总结了通过线粒体靶向策略(如代谢重塑、生物生成增强、抗氧化和活性氧调节)恢复衰竭T细胞功能的最新进展,旨在逆转T细胞衰竭状态,改善对免疫疗法的反应。深入了解线粒体在T细胞衰竭中的作用为开发新型线粒体靶向疗法奠定了基础,也为癌症免疫疗法揭开了新的篇章。
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引用次数: 0
Stool and blood biomarkers for colorectal cancer management: an update on screening and disease monitoring. 用于结直肠癌管理的粪便和血液生物标记物:筛查和疾病监测的最新进展。
IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1186/s12943-024-02174-w
Alessandro Mannucci, Ajay Goel

Background: Biomarkers have revolutionized the management of colorectal cancer (CRC), facilitating early detection, prevention, personalized treatment, and minimal residual disease (MRD) monitoring. This review explores current CRC screening strategies and emerging biomarker applications.

Main body: We summarize the landscape of non-invasive CRC screening and MRD detection strategies, discuss the limitations of the current approaches, and highlight the promising potential of novel biomarker solutions. The fecal immunochemical test remained the cornerstone of CRC screening, but its sensitivity has been improved by assays that combined its performance with other stool analytes. However, their sensitivity for advanced adenomas and the patient compliance both remain suboptimal. Blood-based tests promise to increase compliance but require further refinement to compete with stool-based biomarker tests. The ideal scenario involves leveraging blood tests to increase screening participation, and simultaneously promote stool- and endoscopy-based screening among those who are compliant. Once solely reliant on upfront surgery followed by stage and pathology-driven adjuvant chemotherapy, the treatment of stage II and III colon cancer has undergone a revolutionary transformation with the advent of MRD testing after surgery. A decade ago, the concept of using a post-surgical test instead of stage and pathology to determine the need for adjuvant chemotherapy was disruptive. Today, a blood test may be more informative of the need for chemotherapy than the stage at diagnosis.

Conclusion: Biomarker research is not just improving, but bringing a transformative change to CRC clinical management. Early detection is not just getting better, but improving thanks to a multi-modality approach, and personalized treatment plans are not just becoming a reality, but a promising future with MRD testing.

背景:生物标记物彻底改变了结直肠癌(CRC)的治疗,促进了早期检测、预防、个性化治疗和最小残留病(MRD)监测。这篇综述探讨了当前的 CRC 筛查策略和新兴的生物标记物应用:我们总结了无创 CRC 筛查和 MRD 检测策略的概况,讨论了当前方法的局限性,并强调了新型生物标记物解决方案的巨大潜力。粪便免疫化学检验仍是 CRC 筛查的基石,但其灵敏度已通过将粪便免疫化学检验的性能与其他粪便分析物相结合而得到提高。然而,它们对晚期腺瘤的灵敏度和患者的依从性仍不理想。基于血液的检测有望提高依从性,但需要进一步改进才能与基于粪便的生物标记物检测相抗衡。理想的情况是,利用血液检测提高筛查参与率,同时在符合筛查要求的患者中推广粪便和内镜筛查。II期和III期结肠癌的治疗曾一度完全依赖于前期手术,然后根据分期和病理情况进行辅助化疗,但随着术后MRD检测的出现,这种治疗方法发生了革命性的转变。十年前,用术后检测代替分期和病理来决定是否需要辅助化疗的概念是颠覆性的。如今,血液检测可能比诊断时的分期更能说明化疗的必要性:生物标志物研究不仅在不断进步,而且为 CRC 临床管理带来了变革。得益于多模式方法,早期检测不仅在不断完善,而且在不断改进,而个性化治疗方案不仅正在成为现实,而且通过 MRD 检测前景广阔。
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引用次数: 0
Uncovering the predictive and immunomodulatory potential of transient receptor potential melastatin family-related CCNE1 in pan-cancer. 揭示瞬时受体电位美司他丁家族相关 CCNE1 在泛癌症中的预测和免疫调节潜力。
IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-18 DOI: 10.1186/s12943-024-02169-7
Nan Zhang, Hao Zhang, Shuyu Li, Wantao Wu, Peng Luo, Zaoqu Liu, Yu Chen, Zhiwei Xia, Chenshen Huang, Quan Cheng

Millions of new cases of cancer are diagnosed worldwide each year, making it a serious public health concern. Developments in customized therapy and early detection have significantly enhanced treatment for and results from cancer. Therefore, it is important to investigate new molecular biomarkers. In this study, we created an efficient transient receptor potential melastatin (TRPM) family members-related TRPM-Score for 17 solid tumors. CCNE1, produced from TRPM-Score, was found to be an exceptional biomarker through several sophisticated machine learning and deep learning computational techniques. TRPM-Score and CCNE1 immunotherapeutic prediction, immunological characteristics, and predictive value were thoroughly assessed. In most cancer types, CCNE1 was a substantially dangerous marker. Additional in vitro tests validated CCNE1's immunomodulatory properties, demonstrating that silencing impeded macrophage movement and decreased PD-L1 expression. Additionally, CCNE1 may accurately predict responses to cancer immunotherapy. These findings indicate that the TRPM family-particularly CCNE1, which is associated with TRPM-is a significant player in the pan-cancer domain and can be utilized as a therapeutic target and prognostic biomarkers, especially in immuno-oncology. The thorough characterization of the TRPM family and the discovery of CCNE1 as a crucial downstream effector mark important developments in our comprehension of pan-cancer biology.

全世界每年新增数百万例癌症病例,成为严重的公共卫生问题。定制疗法和早期检测的发展大大提高了癌症的治疗效果。因此,研究新的分子生物标志物非常重要。在这项研究中,我们为 17 种实体瘤创建了有效的瞬时受体电位美司他汀(TRPM)家族成员相关 TRPM-Score 。通过几种复杂的机器学习和深度学习计算技术,我们发现由 TRPM-Score 生成的 CCNE1 是一种特殊的生物标记物。研究人员对TRPM-Score和CCNE1的免疫治疗预测、免疫学特征和预测价值进行了全面评估。在大多数癌症类型中,CCNE1都是一个非常危险的标志物。其他体外测试也验证了CCNE1的免疫调节特性,证明沉默会阻碍巨噬细胞的移动并降低PD-L1的表达。此外,CCNE1 还能准确预测对癌症免疫疗法的反应。这些研究结果表明,TRPM家族,特别是与TRPM相关的CCNE1,在泛癌症领域发挥着重要作用,可被用作治疗靶点和预后生物标志物,尤其是在免疫肿瘤学领域。对TRPM家族的深入研究以及发现CCNE1是一个重要的下游效应因子,标志着我们在理解泛癌症生物学方面取得了重要进展。
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引用次数: 0
Cuproptosis, ferroptosis and PANoptosis in tumor immune microenvironment remodeling and immunotherapy: culprits or new hope. 肿瘤免疫微环境重塑和免疫疗法中的杯突、铁突和泛凋亡:罪魁祸首还是新希望?
IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-15 DOI: 10.1186/s12943-024-02130-8
Xiaojie Zhang, Bufu Tang, Jinhua Luo, Yang Yang, Qiaoyou Weng, Shiji Fang, Zhongwei Zhao, Jianfei Tu, Minjiang Chen, Jiansong Ji

Normal life requires cell division to produce new cells, but cell death is necessary to maintain balance. Dysregulation of cell death can lead to the survival and proliferation of abnormal cells, promoting tumor development. Unlike apoptosis, necrosis, and autophagy, the newly recognized forms of regulated cell death (RCD) cuproptosis, ferroptosis, and PANoptosis provide novel therapeutic strategies for tumor treatment. Increasing research indicates that the death of tumor and immune cells mediated by these newly discovered forms of cell death can regulate the tumor microenvironment (TME) and influence the effectiveness of tumor immunotherapy. This review primarily elucidates the molecular mechanisms of cuproptosis, ferroptosis, and PANoptosis and their complex effects on tumor cells and the TME. This review also summarizes the exploration of nanoparticle applications in tumor therapy based on in vivo and in vitro evidence derived from the induction or inhibition of these new RCD pathways.

正常生命需要细胞分裂来产生新细胞,但细胞死亡是维持平衡的必要条件。细胞死亡失调会导致异常细胞的存活和增殖,促进肿瘤的发展。与细胞凋亡、坏死和自噬不同,新发现的调节性细胞死亡(RCD)形式--杯凋亡、铁凋亡和泛凋亡为肿瘤治疗提供了新的治疗策略。越来越多的研究表明,由这些新发现的细胞死亡形式介导的肿瘤细胞和免疫细胞的死亡可调节肿瘤微环境(TME)并影响肿瘤免疫疗法的效果。本综述主要阐明杯突、铁突和泛凋亡的分子机制及其对肿瘤细胞和肿瘤微环境的复杂影响。本综述还根据诱导或抑制这些新 RCD 通路的体内和体外证据,总结了纳米粒子在肿瘤治疗中的应用探索。
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引用次数: 0
Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma 单细胞和空间转录组学发现COL6A3是未分化多形性肉瘤的预后生物标志物
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-15 DOI: 10.1186/s12943-024-02168-8
Jason C. Klein, Lei Wang, Douglas Strand, Chewlan Lastufka, Gregory A. Hosler, Gary C. Hon
Undifferentiated pleomorphic sarcoma (UPS) and related tumors are the most common type of soft tissue sarcoma. However, this spectrum of tumors has different etiologies with varying rates of metastasis and survival. Two dermal-based neoplasms in this class of pleomorphic sarcomas, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS), are challenging to differentiate at initial biopsy but vary significantly in prognosis. We performed single-cell transcriptomics on five AFX and PDS biopsy specimens as well as both single-cell and spatial transcriptomics on one PDS excision specimen to better characterize these tumors. The top differential genes between AFX and PDS were predictive of overall survival in 17 other cancers included in the Human Protein Atlas. Of these genes, COL6A3 and BGN predicted overall survival and metastasis-free survival in independent cohorts of 46 and 38 UPS tumors, respectively. COL6A3 was most predictive of overall survival in UPS patients and outperformed an established sarcoma prognostic gene panel at predicting metastasis in UPS.
未分化多形性肉瘤(UPS)和相关肿瘤是最常见的软组织肉瘤类型。然而,这类肿瘤的病因不同,转移率和存活率也各异。这一类多形性肉瘤中有两种基于真皮的肿瘤,即非典型纤维黄瘤(AFX)和多形性真皮肉瘤(PDS),它们在最初的活检中很难区分,但预后却有很大差异。我们对五例 AFX 和 PDS 活检标本进行了单细胞转录组学研究,并对一例 PDS 切除标本进行了单细胞和空间转录组学研究,以更好地描述这些肿瘤的特征。AFX和PDS之间差异最大的基因可预测人类蛋白质图谱(Human Protein Atlas)中其他17种癌症的总生存率。在这些基因中,COL6A3和BGN分别预测了46个和38个UPS肿瘤独立组群的总生存率和无转移生存率。COL6A3最能预测UPS患者的总生存期,在预测UPS转移方面优于已建立的肉瘤预后基因小组。
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引用次数: 0
Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer. 针对肺癌 FGF/FGFR 信号转导的临床进展与挑战。
IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-15 DOI: 10.1186/s12943-024-02167-9
Mei Peng, Jun Deng, Xiangping Li

Fibroblast growth factors (FGFs) and their receptors regulate numerous cellular processes, such as metabolism and signal transduction, but can also drive tumorigenesis. Specifically, in lung cancer, the overexpression of FGFs, as well as the amplification, mutation and fusion of FGFR genes, are closely linked to the initiation, progression and resistance of the disease, suggesting that targeting FGF/FGFR is an attractive therapeutic strategy for lung cancer treatment. Nintedanib, a multitarget tyrosine kinase inhibitor (TKI) used in combination with docetaxel, has shown some success as a second-line therapy for lung cancer. However, clinical trials evaluating other FGFR inhibitors have yielded mixed results, indicating substantial complexity in targeting aberrant FGF/FGFR signaling. In this review, we describe the aberrations in FGF/FGFR signaling in lung cancer and summarize the clinical efficacy of FGFR inhibitors, such as multitarget TKIs, selective FGFR-TKIs and biological agents. We also discuss various challenges associated with FGFR targeting in lung cancer, including precision patient selection, toxicity and resistance. Finally, we provide perspectives on future directions, namely, developing novel FGFR-targeting drugs, such as FGFR degraders and more specific FGFR-TKIs, adopting combination therapy and targeting FGFs.

成纤维细胞生长因子(FGFs)及其受体调控着新陈代谢和信号转导等多种细胞过程,但也能驱动肿瘤发生。具体来说,在肺癌中,成纤维细胞生长因子的过度表达以及成纤维细胞生长因子受体基因的扩增、突变和融合与疾病的发生、发展和耐药性密切相关,这表明靶向成纤维细胞生长因子/成纤维细胞生长因子受体是一种有吸引力的肺癌治疗策略。Nintedanib是一种多靶点酪氨酸激酶抑制剂(TKI),与多西他赛联合使用,作为肺癌的二线疗法取得了一定的成功。然而,评估其他表皮生长因子受体抑制剂的临床试验结果喜忧参半,这表明靶向异常表皮生长因子/表皮生长因子受体信号转导的过程非常复杂。在这篇综述中,我们描述了肺癌中 FGF/FGFR 信号的畸变,并总结了 FGFR 抑制剂(如多靶点 TKIs、选择性 FGFR-TKIs 和生物制剂)的临床疗效。我们还讨论了肺癌 FGFR 靶向治疗面临的各种挑战,包括患者的精准选择、毒性和耐药性。最后,我们展望了未来的发展方向,即开发新型 FGFR 靶向药物,如 FGFR 降解剂和更具特异性的 FGFR-TKIs,采用联合疗法和靶向 FGFs。
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Molecular Cancer
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