Pub Date : 2024-06-27DOI: 10.1186/s12943-024-02042-7
Robin Mjelle, Are K. Kristensen, Tora S. Solheim, Ganna S. Westvik, Hege Elvebakken, Eva Hofsli
Metastatic colorectal cancer (mCRC) presents significant challenges in clinical management due to its heterogeneity and variable response to treatment. In this study, we conducted comprehensive small RNA (sRNA) sequencing analyses to identify sRNA biomarkers associated with survival and treatment response in mCRC patients. We measured serum sRNAs before and after chemotherapy treatment in a discovery cohort of 189 mCRC patients. Our analysis revealed 25 microRNAs (miRNA) as significantly associated with overall survival at baseline. We found that 11 of the 25 significant miRNAs were also significant in an independent validation cohort of 20 mCRC patients, including the top five miRNAs from the discovery cohort. Importantly, all but four of the 25 significant miRNAs from the discovery cohort had hazard ratios in the same direction in the validation cohort. Among the 25 significant miRNAs, we identified the miR-320 family of miRNAs as the strongest independent prognostic marker, with high baseline levels correlating with poor survival outcomes. Furthermore, post-treatment levels of the same miRNAs were even more predictive of overall survival, emphasizing the prognostic value of serum changes in miRNA levels before and after treatment. Moreover, we observed significant changes in serum miRNAs and other sRNAs when comparing samples before and after chemotherapy, with distinct expression patterns between responders and non-responders. Leveraging these differential expression patterns, we established a serum sRNA signature that accurately predicts response to chemotherapy with an area under the curve (AUC) of 0.8. In summary, our study highlights the prognostic and predictive potential of sRNA biomarkers in mCRC, offering valuable insights into patient stratification and personalized treatment approaches.
{"title":"Serum small RNAs in metastatic colorectal cancer predict response to chemotherapy and characterize high-risk patients","authors":"Robin Mjelle, Are K. Kristensen, Tora S. Solheim, Ganna S. Westvik, Hege Elvebakken, Eva Hofsli","doi":"10.1186/s12943-024-02042-7","DOIUrl":"https://doi.org/10.1186/s12943-024-02042-7","url":null,"abstract":"Metastatic colorectal cancer (mCRC) presents significant challenges in clinical management due to its heterogeneity and variable response to treatment. In this study, we conducted comprehensive small RNA (sRNA) sequencing analyses to identify sRNA biomarkers associated with survival and treatment response in mCRC patients. We measured serum sRNAs before and after chemotherapy treatment in a discovery cohort of 189 mCRC patients. Our analysis revealed 25 microRNAs (miRNA) as significantly associated with overall survival at baseline. We found that 11 of the 25 significant miRNAs were also significant in an independent validation cohort of 20 mCRC patients, including the top five miRNAs from the discovery cohort. Importantly, all but four of the 25 significant miRNAs from the discovery cohort had hazard ratios in the same direction in the validation cohort. Among the 25 significant miRNAs, we identified the miR-320 family of miRNAs as the strongest independent prognostic marker, with high baseline levels correlating with poor survival outcomes. Furthermore, post-treatment levels of the same miRNAs were even more predictive of overall survival, emphasizing the prognostic value of serum changes in miRNA levels before and after treatment. Moreover, we observed significant changes in serum miRNAs and other sRNAs when comparing samples before and after chemotherapy, with distinct expression patterns between responders and non-responders. Leveraging these differential expression patterns, we established a serum sRNA signature that accurately predicts response to chemotherapy with an area under the curve (AUC) of 0.8. In summary, our study highlights the prognostic and predictive potential of sRNA biomarkers in mCRC, offering valuable insights into patient stratification and personalized treatment approaches.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461990","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}
Pub Date : 2024-06-26DOI: 10.1186/s12943-024-02047-2
Zhaokai Zhou, Jiahui Wang, Jiaojiao Wang, Shuai Yang, Ruizhi Wang, Ge Zhang, Zhengrui Li, Run Shi, Zhan Wang, Qiong Lu
Tumor immune microenvironment (TIME) consists of intra-tumor immunological components and plays a significant role in tumor initiation, progression, metastasis, and response to therapy. Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the cancer treatment paradigm. Although CAR-T cell immunotherapy has emerged as a successful treatment for hematologic malignancies, it remains a conundrum for solid tumors. The heterogeneity of TIME is responsible for poor outcomes in CAR-T cell immunotherapy against solid tumors. The advancement of highly sophisticated technology enhances our exploration in TIME from a multi-omics perspective. In the era of machine learning, multi-omics studies could reveal the characteristics of TIME and its immune resistance mechanism. Therefore, the clinical efficacy of CAR-T cell immunotherapy in solid tumors could be further improved with strategies that target unfavorable conditions in TIME. Herein, this review seeks to investigate the factors influencing TIME formation and propose strategies for improving the effectiveness of CAR-T cell immunotherapy through a multi-omics perspective, with the ultimate goal of developing personalized therapeutic approaches.
肿瘤免疫微环境（TIME）由肿瘤内免疫成分组成，在肿瘤的发生、发展、转移和治疗反应中发挥着重要作用。嵌合抗原受体（CAR）-T 细胞免疫疗法彻底改变了癌症治疗模式。虽然 CAR-T 细胞免疫疗法已成功治疗了血液系统恶性肿瘤，但对于实体瘤来说，它仍然是一个难题。TIME的异质性是CAR-T细胞免疫疗法治疗实体瘤疗效不佳的原因。高精尖技术的进步加强了我们从多组学角度对 TIME 的探索。在机器学习时代，多组学研究可以揭示 TIME 的特征及其免疫耐受机制。因此，针对TIME中的不利条件采取相应策略，可进一步提高CAR-T细胞免疫疗法在实体瘤中的临床疗效。在此，本综述旨在通过多组学视角研究影响TIME形成的因素，并提出提高CAR-T细胞免疫疗法疗效的策略，最终实现开发个性化治疗方法的目标。
{"title":"Deciphering the tumor immune microenvironment from a multidimensional omics perspective: insight into next-generation CAR-T cell immunotherapy and beyond.","authors":"Zhaokai Zhou, Jiahui Wang, Jiaojiao Wang, Shuai Yang, Ruizhi Wang, Ge Zhang, Zhengrui Li, Run Shi, Zhan Wang, Qiong Lu","doi":"10.1186/s12943-024-02047-2","DOIUrl":"10.1186/s12943-024-02047-2","url":null,"abstract":"<p><p>Tumor immune microenvironment (TIME) consists of intra-tumor immunological components and plays a significant role in tumor initiation, progression, metastasis, and response to therapy. Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the cancer treatment paradigm. Although CAR-T cell immunotherapy has emerged as a successful treatment for hematologic malignancies, it remains a conundrum for solid tumors. The heterogeneity of TIME is responsible for poor outcomes in CAR-T cell immunotherapy against solid tumors. The advancement of highly sophisticated technology enhances our exploration in TIME from a multi-omics perspective. In the era of machine learning, multi-omics studies could reveal the characteristics of TIME and its immune resistance mechanism. Therefore, the clinical efficacy of CAR-T cell immunotherapy in solid tumors could be further improved with strategies that target unfavorable conditions in TIME. Herein, this review seeks to investigate the factors influencing TIME formation and propose strategies for improving the effectiveness of CAR-T cell immunotherapy through a multi-omics perspective, with the ultimate goal of developing personalized therapeutic approaches.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11201788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450976","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}
TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.
TFE3重排肾细胞癌（TFE3-rRCC）是一种罕见但高度异质性的肾细胞癌（RCC）实体，其临床治疗前景在很大程度上尚未明确。本研究旨在评估和比较不同系统治疗方法的疗效，并进一步探讨其分子相关性。研究共纳入38例转移性TFE3-rRCC患者。主要结果包括无进展生存期（PFS）、总生存期、客观反应率（ORR）和疾病控制率。对32个肿瘤进行了RNA测序。接受基于免疫检查点抑制剂（ICI）的一线联合疗法的患者比未接受ICI治疗的患者获得了更长的PFS（中位PFS：11.5个月 vs. 5.1个月，P = 0.098）。在对融合伙伴进行分层后，基于 ICI 的一线联合疗法的卓越疗效主要在 ASPSCR1-TFE3 rRCC 中观察到（中位 PFS：未达到 vs. 6.5 个月，P = 0.01；ORR：67.5% vs. 10.0%，P = 0.019），但在非 ASPSCR1-TFE3 rRCC 中几乎没有观察到。转录组数据显示，ASPSCR1-TFE3 rRCC中与ECM和胶原蛋白相关的信号转导丰富，这可能会干扰抗血管生成单药的潜在疗效。而血管生成和免疫活动在ASPSCR1-TFE3型rRCC中完全富集，这就保证了ICI加酪氨酸激酶抑制剂联合疗法能取得更好的临床疗效。目前的研究是基于融合伙伴分层比较转移性TFE3-rRCC治疗效果并研究其分子相关性的最大队列。基于 ICI 的联合疗法可作为转移性 ASPSCR1-TFE3 rRCC 患者的有效一线治疗方案。对于其他融合亚型，应进一步研究其分子机制，从而提出相应的治疗策略。
{"title":"Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma","authors":"Junjie Zhao, Yanfeng Tang, Xu Hu, Xiaoxue Yin, Yuntian Chen, Junru Chen, Haoyang Liu, Haolin Liu, Jiayu Liang, Xingming Zhang, Jinge Zhao, Sha Zhu, Yuchao Ni, Zhipeng Wang, Jindong Dai, Zilin Wang, Yaowen Zhang, Jin Yao, Ni Chen, Pengfei Shen, Zhenhua H. Liu, Hao Zeng, Guangxi X. Sun","doi":"10.1186/s12943-024-02044-5","DOIUrl":"https://doi.org/10.1186/s12943-024-02044-5","url":null,"abstract":"TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452979","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}
Pub Date : 2024-06-20DOI: 10.1186/s12943-024-02040-9
Yang Jin, Yuanli Zuo, Gang Li, Wenrong Liu, Yitong Pan, Ting Fan, Xin Fu, Xiaojun Yao, Yong Peng
Malignant tumors have increasing morbidity and high mortality, and their occurrence and development is a complicate process. The development of sequencing technologies enabled us to gain a better understanding of the underlying genetic and molecular mechanisms in tumors. In recent years, the spatial transcriptomics sequencing technologies have been developed rapidly and allow the quantification and illustration of gene expression in the spatial context of tissues. Compared with the traditional transcriptomics technologies, spatial transcriptomics technologies not only detect gene expression levels in cells, but also inform the spatial location of genes within tissues, cell composition of biological tissues, and interaction between cells. Here we summarize the development of spatial transcriptomics technologies, spatial transcriptomics tools and its application in cancer research. We also discuss the limitations and challenges of current spatial transcriptomics approaches, as well as future development and prospects.
{"title":"Advances in spatial transcriptomics and its applications in cancer research","authors":"Yang Jin, Yuanli Zuo, Gang Li, Wenrong Liu, Yitong Pan, Ting Fan, Xin Fu, Xiaojun Yao, Yong Peng","doi":"10.1186/s12943-024-02040-9","DOIUrl":"https://doi.org/10.1186/s12943-024-02040-9","url":null,"abstract":"Malignant tumors have increasing morbidity and high mortality, and their occurrence and development is a complicate process. The development of sequencing technologies enabled us to gain a better understanding of the underlying genetic and molecular mechanisms in tumors. In recent years, the spatial transcriptomics sequencing technologies have been developed rapidly and allow the quantification and illustration of gene expression in the spatial context of tissues. Compared with the traditional transcriptomics technologies, spatial transcriptomics technologies not only detect gene expression levels in cells, but also inform the spatial location of genes within tissues, cell composition of biological tissues, and interaction between cells. Here we summarize the development of spatial transcriptomics technologies, spatial transcriptomics tools and its application in cancer research. We also discuss the limitations and challenges of current spatial transcriptomics approaches, as well as future development and prospects.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430417","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}
RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating RNA splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of RNA methylation on tumor immunity. The primary types of RNA methylation encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G), and 3-methylcytidine (m3C). Compelling evidence underscores the involvement of RNA methylation in regulating the tumor microenvironment (TME). By affecting RNA translation and stability through the "writers", "erasers" and "readers", RNA methylation exerts influence over the dysregulation of immune cells and immune factors. Consequently, RNA methylation plays a pivotal role in modulating tumor immunity and mediating various biological behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed the mechanisms and functions of several RNA methylations, providing a comprehensive overview of their biological roles and underlying mechanisms within the tumor microenvironment and among immunocytes. By exploring how these RNA modifications mediate tumor immune evasion, we also examine their potential applications in immunotherapy. This review aims to provide novel insights and strategies for identifying novel targets in RNA methylation and advancing cancer immunotherapy efficacy.
{"title":"The role of RNA methylation in tumor immunity and its potential in immunotherapy","authors":"Yan Li, Haoer Jin, Qingling Li, Liangrong Shi, Yitao Mao, Luqing Zhao","doi":"10.1186/s12943-024-02041-8","DOIUrl":"https://doi.org/10.1186/s12943-024-02041-8","url":null,"abstract":"RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating RNA splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of RNA methylation on tumor immunity. The primary types of RNA methylation encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G), and 3-methylcytidine (m3C). Compelling evidence underscores the involvement of RNA methylation in regulating the tumor microenvironment (TME). By affecting RNA translation and stability through the \"writers\", \"erasers\" and \"readers\", RNA methylation exerts influence over the dysregulation of immune cells and immune factors. Consequently, RNA methylation plays a pivotal role in modulating tumor immunity and mediating various biological behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed the mechanisms and functions of several RNA methylations, providing a comprehensive overview of their biological roles and underlying mechanisms within the tumor microenvironment and among immunocytes. By exploring how these RNA modifications mediate tumor immune evasion, we also examine their potential applications in immunotherapy. This review aims to provide novel insights and strategies for identifying novel targets in RNA methylation and advancing cancer immunotherapy efficacy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430416","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}
Circular RNAs (circRNAs) play important roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear. In this study, we identified a novel circRNA, hsa_circ_0006834 (termed circ6834), in NSCLC by RNA-seq and investigated the biological role of circ6834 in NSCLC progression in vitro and in vivo. Finally, the molecular mechanism of circ6834 was revealed by tagged RNA affinity purification (TRAP), western blot, RNA immunoprecipitation, dual luciferase reporter gene assays and rescue experiments. Our results showed that circ6834 was downregulated in NSCLC tumor tissues and cell lines. Circ6834 overexpression inhibited NSCLC cell growth and metastasis both in vitro and in vivo, while circ6834 knockdown had the opposite effect. We found that TGF-β treatment decreased circ6834 expression, which was associated with the QKI reduction in NSCLC cells and circ6834 antagonized TGF-β-induced EMT and metastasis in NSCLC cells. Mechanistically, circ6834 bound to AHNAK protein, a key regulator of TGF-β/Smad signaling, and inhibited its stability by enhancing TRIM25-mediated ubiquitination and degradation. In addition, circ6834 acted as a miRNA sponge for miR-873-5p and upregulated TXNIP gene expression, which together inactivated the TGF-β/Smad signaling pathway in NSCLC cells. In conclusion, circ6834 is a tumor-suppressive circRNA that inhibits NSCLC progression by forming a negative regulatory feedback loop with the TGF-β/Smad signaling pathway and represents a novel therapeutic target for NSCLC.
{"title":"Circ6834 suppresses non-small cell lung cancer progression by destabilizing ANHAK and regulating miR-873-5p/TXNIP axis","authors":"Maoye Wang, Xiaoge Ding, Xinjian Fang, Jing Xu, Yanke Chen, Yu Qian, Jiahui Zhang, Dan Yu, Xiaoxin Zhang, Xiuqin Ma, Taofeng Zhu, Jianmei Gu, Xu Zhang","doi":"10.1186/s12943-024-02038-3","DOIUrl":"https://doi.org/10.1186/s12943-024-02038-3","url":null,"abstract":"Circular RNAs (circRNAs) play important roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear. In this study, we identified a novel circRNA, hsa_circ_0006834 (termed circ6834), in NSCLC by RNA-seq and investigated the biological role of circ6834 in NSCLC progression in vitro and in vivo. Finally, the molecular mechanism of circ6834 was revealed by tagged RNA affinity purification (TRAP), western blot, RNA immunoprecipitation, dual luciferase reporter gene assays and rescue experiments. Our results showed that circ6834 was downregulated in NSCLC tumor tissues and cell lines. Circ6834 overexpression inhibited NSCLC cell growth and metastasis both in vitro and in vivo, while circ6834 knockdown had the opposite effect. We found that TGF-β treatment decreased circ6834 expression, which was associated with the QKI reduction in NSCLC cells and circ6834 antagonized TGF-β-induced EMT and metastasis in NSCLC cells. Mechanistically, circ6834 bound to AHNAK protein, a key regulator of TGF-β/Smad signaling, and inhibited its stability by enhancing TRIM25-mediated ubiquitination and degradation. In addition, circ6834 acted as a miRNA sponge for miR-873-5p and upregulated TXNIP gene expression, which together inactivated the TGF-β/Smad signaling pathway in NSCLC cells. In conclusion, circ6834 is a tumor-suppressive circRNA that inhibits NSCLC progression by forming a negative regulatory feedback loop with the TGF-β/Smad signaling pathway and represents a novel therapeutic target for NSCLC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334131","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}
The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1low/CAMSAP3low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1low/CAMSAP3low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.
{"title":"Multi-omics profiling reveal cells with novel oncogenic cluster, TRAP1<sup>low</sup>/CAMSAP3<sup>low</sup>, emerge more aggressive behavior and poor-prognosis in early-stage endometrial cancer.","authors":"Xiaodan Mao, Xiaoyue Tang, Jingxuan Ye, Shuxia Xu, Yue Wang, Xianhua Liu, Qibin Wu, Xite Lin, Maotong Zhang, Jiangfeng Liu, Juntao Yang, Pengming Sun","doi":"10.1186/s12943-024-02039-2","DOIUrl":"10.1186/s12943-024-02039-2","url":null,"abstract":"<p><p>The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1<sup>low</sup>/CAMSAP3<sup>low</sup> cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1<sup>low</sup>/CAMSAP3<sup>low</sup> cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11181528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141331477","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}
In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.
{"title":"Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations","authors":"Syuzo Kaneko, Ken Takasawa, Ken Asada, Kouya Shiraishi, Noriko Ikawa, Hidenori Machino, Norio Shinkai, Maiko Matsuda, Mari Masuda, Shungo Adachi, Satoshi Takahashi, Kazuma Kobayashi, Nobuji Kouno, Amina Bolatkan, Masaaki Komatsu, Masayoshi Yamada, Mototaka Miyake, Hirokazu Watanabe, Akiko Tateishi, Takaaki Mizuno, Yu Okubo, Masami Mukai, Tatsuya Yoshida, Yukihiro Yoshida, Hidehito Horinouchi, Shun-Ichi Watanabe, Yuichiro Ohe, Yasushi Yatabe, Vassiliki Saloura, Takashi Kohno, Ryuji Hamamoto","doi":"10.1186/s12943-024-02035-6","DOIUrl":"https://doi.org/10.1186/s12943-024-02035-6","url":null,"abstract":"In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141304328","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}
Pub Date : 2024-06-10DOI: 10.1186/s12943-024-02028-5
Rashmi Bharti, Goutam Dey, Debjit Khan, Alex Myers, Olivia G Huffman, Caner Saygin, Chad Braley, Elliott Richards, Naseer Sangwan, Belinda Willard, Justin D Lathia, Paul L Fox, Feng Lin, Babal Kant Jha, J Mark Brown, Jennifer S Yu, Mohammed Dwidar, Amy Joehlin-Price, Roberto Vargas, Chad M Michener, Michelle S Longworth, Ofer Reizes
Background: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers.
Methods: Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing.
Results: CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, stemness, and cell proliferation in OC cells. CD55 S/T domain is necessary for nuclear entry and inducing chemoresistance to cisplatin in both in vitro and in vivo models. Deletion of the CD55 S/T domain is sufficient to sensitize chemoresistant OC cells to cisplatin. In the nucleus, CD55 binds and attenuates the epigenetic regulator and tumor suppressor ZMYND8 with a parallel increase in H3K27 trimethylation and members of the Polycomb Repressive Complex 2.
Conclusions: For the first time, we show CD55 localizes to the nucleus in OC and promotes CSC and chemoresistance. Our studies identify a therapeutic mechanism for treating platinum resistant ovarian cancer by blocking CD55 nuclear entry.
{"title":"Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.","authors":"Rashmi Bharti, Goutam Dey, Debjit Khan, Alex Myers, Olivia G Huffman, Caner Saygin, Chad Braley, Elliott Richards, Naseer Sangwan, Belinda Willard, Justin D Lathia, Paul L Fox, Feng Lin, Babal Kant Jha, J Mark Brown, Jennifer S Yu, Mohammed Dwidar, Amy Joehlin-Price, Roberto Vargas, Chad M Michener, Michelle S Longworth, Ofer Reizes","doi":"10.1186/s12943-024-02028-5","DOIUrl":"10.1186/s12943-024-02028-5","url":null,"abstract":"<p><strong>Background: </strong>Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers.</p><p><strong>Methods: </strong>Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing.</p><p><strong>Results: </strong>CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, stemness, and cell proliferation in OC cells. CD55 S/T domain is necessary for nuclear entry and inducing chemoresistance to cisplatin in both in vitro and in vivo models. Deletion of the CD55 S/T domain is sufficient to sensitize chemoresistant OC cells to cisplatin. In the nucleus, CD55 binds and attenuates the epigenetic regulator and tumor suppressor ZMYND8 with a parallel increase in H3K27 trimethylation and members of the Polycomb Repressive Complex 2.</p><p><strong>Conclusions: </strong>For the first time, we show CD55 localizes to the nucleus in OC and promotes CSC and chemoresistance. Our studies identify a therapeutic mechanism for treating platinum resistant ovarian cancer by blocking CD55 nuclear entry.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296463","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}
Pub Date : 2024-06-08DOI: 10.1186/s12943-024-02037-4
Yiran Liang, Fangzhou Ye, Dan Luo, Li Long, Yajie Wang, Yuhan Jin, Lei Wang, Yaming Li, Dianwen Han, Bing Chen, Wenjing Zhao, Lijuan Wang, Qifeng Yang
Background: Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated.
Methods: RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3.
Results: Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients.
Conclusions: Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.
{"title":"Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer.","authors":"Yiran Liang, Fangzhou Ye, Dan Luo, Li Long, Yajie Wang, Yuhan Jin, Lei Wang, Yaming Li, Dianwen Han, Bing Chen, Wenjing Zhao, Lijuan Wang, Qifeng Yang","doi":"10.1186/s12943-024-02037-4","DOIUrl":"10.1186/s12943-024-02037-4","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated.</p><p><strong>Methods: </strong>RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3.</p><p><strong>Results: </strong>Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients.</p><p><strong>Conclusions: </strong>Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11161950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288356","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}
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