Cancer letters最新文献

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Corrigendum to “Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer [Cancer Lett. 379 (2016) 1–11]

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-20 DOI: 10.1016/j.canlet.2025.217562

Huai-Qiang Ju , Zhuo-Nan Zhuang , Hao Li , Tian Tian , Yun-Xin Lu , Xiao-Qiang Fan , Hai-Jun Zhou , Hai-Yu Mo , Hui Sheng , Paul J. Chiao , Rui-Hua Xu

引用次数: 0

Intracellular and extracellular activities of V-domain Ig-containing suppressor of T cell activation (VISTA) modulated by immunosuppressive factors of tumour microenvironment

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-20 DOI: 10.1016/j.canlet.2025.217581

Maryam Abooali , Stephanie Schlichtner , Xi Lei , Nijas Aliu , Sabrina Ruggiero , Sonia Loges , Martin Ziegler , Franziska Hertel , Anna-Lena Volckmar , Albrecht Stenzinger , Petros Christopoulos , Michael Thomas , Elena Klenova , N. Helge Meyer , Stergios Boussios , Nigel Heaton , Yoh Zen , Ane Zamalloa , Shilpa Chokshi , Luca Urbani , Vadim V. Sumbayev

V-domain Ig-containing suppressor of T cell activation (VISTA) is a unique immune checkpoint protein, which was reported to display both receptor and ligand activities. However, the mechanisms of regulation of VISTA activity and functions by factors of tumour microenvironment (TME) remain unclear and understanding these processes is required in order to develop successful personalised cancer immunotherapeutic strategies and approaches. Here we report for the very first time that VISTA interacts with another immune checkpoint protein galectin-9 inside the cell most likely facilitating its interaction with TGF-β-activated kinase 1 (TAK1). This process is required for protection of lysosomes, which is crucial for many cell types and tissues. We found that VISTA expression can be differentially controlled by crucial factors present in TME, such as transforming growth factor beta type 1 (TGF-β) and hypoxia as well as other factors activating hypoxic signalling. We confirmed that involvement of these important pathways modulated by TME differentially influences VISTA expression in different cell types. These networks include: TGF-β-Smad3 pathway, TAK1 (TGF-β-activated kinase 1) or apoptosis signal-regulating kinase 1 (ASK1)-induced activation of activating transcription factor 2 (ATF-2) and hypoxic signalling pathway. Based on this work we determined the five critical functions of VISTA and the role of TME factors in controlling (modulating or downregulating) VISTA expression.

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引用次数: 0

LIN28B enhances the chemosensitivity of colon cancer cells via inducing genomic instability by upsetting the balance between the production and removal of reactive oxygen species LIN28B 通过破坏活性氧产生和清除之间的平衡，诱导基因组不稳定性，从而增强结肠癌细胞的化疗敏感性。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-20 DOI: 10.1016/j.canlet.2025.217572

Tianzhen Wang , Mingjiao Weng , Kai Li , Guoli Li , Shijie Hu , Ziyi Hu , Yanping Li , Muhan Li , Di Wu , Zhigang Liang , Fei Yu , Guangyu Wang , Xiaobo Li

Genomic instability is an enabling characteristic that allows cancer cells to acquire additional hallmarks of cancer through the accumulation of alterations in driver genes. Furthermore, it creates opportunities to enhance the sensitivity of cancer cells to chemotherapeutic agents targeting DNA, owing to the presence of incomplete DNA damage repair pathways. This study identifies LIN28B as a crucial regulator of colon cancer cells' sensitivity to DNA damage- or repair-related compounds by promoting genomic instability. LIN28B mechanistically reduces glutathione (GSH) synthesis and activity by inhibiting the expression of four GSH metabolic enzymes (GCLC, G6PD, GSTM4, and GSTT2B), thereby reducing the capacity of cells to eliminate reactive oxygen species (ROS). LIN28B enhances the proinflammatory signaling pathway in cancer cells through the upregulation of ARID3A, a transcription factor that transactivates PTGES and PTGES2, resulting in increased production of PGE2, a key inflammatory mediator that can elevate ROS generation. In conclusion, LIN28B altered the equilibrium of ROS production and elimination in colon cancer, resulting in elevated ROS levels and subsequent genomic instability.

基因组不稳定性是一种有利的特性，可使癌细胞通过累积驱动基因的改变而获得更多的癌症特征。此外，由于存在不完整的 DNA 损伤修复途径，基因组不稳定性还能提高癌细胞对针对 DNA 的化疗药物的敏感性。这项研究通过促进基因组不稳定性，发现 LIN28B 是结肠癌细胞对 DNA 损伤或修复相关化合物敏感性的关键调节因子。LIN28B 通过抑制四种谷胱甘肽代谢酶（GCLC、G6PD、GSTM4 和 GSTT2B）的表达，从机理上降低了谷胱甘肽（GSH）的合成和活性，从而降低了细胞消除活性氧（ROS）的能力。LIN28B 通过上调 ARID3A（一种可转录 PTGES 和 PTGES2 的转录因子）来增强癌细胞中的促炎信号通路，从而导致 PGE2（一种可增加 ROS 生成的关键炎症介质）的生成增加。总之，LIN28B 改变了结肠癌中 ROS 生成和消除的平衡，导致 ROS 水平升高，进而导致基因组不稳定。

{"title":"LIN28B enhances the chemosensitivity of colon cancer cells via inducing genomic instability by upsetting the balance between the production and removal of reactive oxygen species","authors":"Tianzhen Wang , Mingjiao Weng , Kai Li , Guoli Li , Shijie Hu , Ziyi Hu , Yanping Li , Muhan Li , Di Wu , Zhigang Liang , Fei Yu , Guangyu Wang , Xiaobo Li","doi":"10.1016/j.canlet.2025.217572","DOIUrl":"10.1016/j.canlet.2025.217572","url":null,"abstract":"<div><div>Genomic instability is an enabling characteristic that allows cancer cells to acquire additional hallmarks of cancer through the accumulation of alterations in driver genes. Furthermore, it creates opportunities to enhance the sensitivity of cancer cells to chemotherapeutic agents targeting DNA, owing to the presence of incomplete DNA damage repair pathways. This study identifies LIN28B as a crucial regulator of colon cancer cells' sensitivity to DNA damage- or repair-related compounds by promoting genomic instability. LIN28B mechanistically reduces glutathione (GSH) synthesis and activity by inhibiting the expression of four GSH metabolic enzymes (GCLC, G6PD, GSTM4, and GSTT2B), thereby reducing the capacity of cells to eliminate reactive oxygen species (ROS). LIN28B enhances the proinflammatory signaling pathway in cancer cells through the upregulation of ARID3A, a transcription factor that transactivates PTGES and PTGES2, resulting in increased production of PGE2, a key inflammatory mediator that can elevate ROS generation. In conclusion, LIN28B altered the equilibrium of ROS production and elimination in colon cancer, resulting in elevated ROS levels and subsequent genomic instability.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217572"},"PeriodicalIF":9.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476323","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

Therapy resistance: Modulating evolutionarily conserved heat shock protein machinery in cancer

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-20 DOI: 10.1016/j.canlet.2025.217571

Ilona Skrabalak , Alicja Rajtak , Beata Malachowska , Natalia Skrzypczak , Karin A. Skalina , Chandan Guha , Jan Kotarski , Karolina Okla

Therapy resistance is a major barrier to achieving a cure in cancer patients, often resulting in relapses and mortality. Heat shock proteins (HSPs) are a group of evolutionarily conserved proteins that play a prominent role in the progression of cancer and drug resistance. HSP synthesis is upregulated in cancer cells, facilitating adaptation to various tumor microenvironment (TME) stressors, including nutrient deprivation, exposure to DNA‐damaging agents, hypoxia, and immune responses. In this review, we present background information about HSP-mediated cancer therapy resistance. Within this context, we emphasize recent progress in the understanding of HSP machinery, exploring the therapeutic potential of HSPs in cancer treatment.

引用次数: 0

SRSF12 deficiency enhances tumor innervation and accelerates pancreatic tumorigenesis

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-20 DOI: 10.1016/j.canlet.2025.217563

Min-Wei Yang , Qin-Yuan Jia , Da-Peng Xu , Yan-Nan Xu , Yan-Miao Huo , De-Jun Liu , Jian-Yu Yang , Xue-Liang Fu , Ding Ma , Zong-Hao Duan , Yi-Fan Yin , Xue-Shi-Yu Ma , Kan Xu , Rong Hua , Jun-Feng Zhang , Yong-Wei Sun , Wei Liu

The peripheral nervous system significantly determines the fate of solid tumors and their microenvironment. In neurotropic malignancies such as pancreatic and prostate cancer, denervation in animal models demonstrate significantly delays in tumor initiation and progression, underscoring the critical neural dependency of these cancers. While tumor innervation establishes a structural basis for the neuromodulatory effects, the degree of innervation exhibits marked heterogeneity across tumor types, and its regulatory mechanisms remain poorly characterized. In this study, we screened genes associated with innervation status in pancreatic cancer and identified the splicing factor SRSF12 as a critical gene related to tumor innervation. In clinical samples, SRSF12 was expressed at low levels in pancreatic cancer tissues, and its downregulation was linked to poor prognosis in patients. Then we crossed Kras mutation and Srsf12 knockout mice (Kras^G12D Srsf12 ^fl/fl) together with Srsf12 ^fl/fl Pdx1^cre mice and found that depletion of Srsf12 accelerated Kras-driven pancreatic tumorigenesis and enhanced tumor innervation. Furthermore, we demonstrated that SRSF12 inhibits neurite outgrowth primarily by generating a LAMA3 splice isoform that lacks the fourth and fifth LG (G45) domains. Mechanistically, G45 promotes tumor innervation by activating ITGB1 and FAK in neurons. Together, our findings delineate SRSF12 as a novel suppressor of tumor innervation and pancreatic tumorigenesis, while also identifying a tumor-specific target for SRSF12-deficient pancreatic cancer.

{"title":"SRSF12 deficiency enhances tumor innervation and accelerates pancreatic tumorigenesis","authors":"Min-Wei Yang , Qin-Yuan Jia , Da-Peng Xu , Yan-Nan Xu , Yan-Miao Huo , De-Jun Liu , Jian-Yu Yang , Xue-Liang Fu , Ding Ma , Zong-Hao Duan , Yi-Fan Yin , Xue-Shi-Yu Ma , Kan Xu , Rong Hua , Jun-Feng Zhang , Yong-Wei Sun , Wei Liu","doi":"10.1016/j.canlet.2025.217563","DOIUrl":"10.1016/j.canlet.2025.217563","url":null,"abstract":"<div><div>The peripheral nervous system significantly determines the fate of solid tumors and their microenvironment. In neurotropic malignancies such as pancreatic and prostate cancer, denervation in animal models demonstrate significantly delays in tumor initiation and progression, underscoring the critical neural dependency of these cancers. While tumor innervation establishes a structural basis for the neuromodulatory effects, the degree of innervation exhibits marked heterogeneity across tumor types, and its regulatory mechanisms remain poorly characterized. In this study, we screened genes associated with innervation status in pancreatic cancer and identified the splicing factor <em>SRSF12</em> as a critical gene related to tumor innervation. In clinical samples, SRSF12 was expressed at low levels in pancreatic cancer tissues, and its downregulation was linked to poor prognosis in patients. Then we crossed <em>Kras</em> mutation and <em>Srsf12</em> knockout mice (<em>Kras</em><sup>G12D</sup> <em>Srsf12</em> <sup>fl/fl</sup>) together with <em>Srsf12</em> <sup>fl/fl</sup> <em>Pdx1</em><sup>cre</sup> mice and found that depletion of <em>Srsf12</em> accelerated <em>Kras</em>-driven pancreatic tumorigenesis and enhanced tumor innervation. Furthermore, we demonstrated that SRSF12 inhibits neurite outgrowth primarily by generating a LAMA3 splice isoform that lacks the fourth and fifth LG (G45) domains. Mechanistically, G45 promotes tumor innervation by activating ITGB1 and FAK in neurons. Together, our findings delineate SRSF12 as a novel suppressor of tumor innervation and pancreatic tumorigenesis, while also identifying a tumor-specific target for SRSF12-deficient pancreatic cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217563"},"PeriodicalIF":9.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476329","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

The biological and technical challenges facing utilizing circulating tumor DNA in non-metastatic breast cancer patients

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-19 DOI: 10.1016/j.canlet.2025.217574

Zihang Zeng , Zongbi Yi , Binghe Xu

Breast cancer is one of the most prevalent cancers and has emerged as a major global challenge. Circulating tumor DNA (ctDNA), a liquid biopsy method, overcomes the accessibility limitations of tissue-based testing and is widely used for monitoring minimal residual disease and molecular relapse, predicting prognosis, evaluating the response of neoadjuvant therapy, and optimizing treatment decisions in non-metastatic breast cancer. However, the application of ctDNA still faces many challenges. Here, we survey the clinical applications of ctDNA in non-metastatic breast cancer and discuss the significant biological and technical challenges of utilizing ctDNA. Importantly, we investigate potential avenues for addressing the challenges. In addition, emerging technologies, including fragmentomics detection, methylation sequencing, and long-read sequencing, have clinical potential and could be a future direction. Proper utilization of machine learning facilitates the identification of meaningful patterns from complex fragment and methylation profiles of ctDNA. There is still a lack of clinical trials focused on the subsets of ctDNA (e.g., circulating mitochondrial DNA), ctDNA-inferred drug-resistant clonal evolution, tumor heterogeneity, and ctDNA-guided clinical decision-making in non-metastatic breast cancer. Due to regional differences in the number of registered clinical trials, it is essential to enhance communication and foster global collaboration to advance the field.

{"title":"The biological and technical challenges facing utilizing circulating tumor DNA in non-metastatic breast cancer patients","authors":"Zihang Zeng , Zongbi Yi , Binghe Xu","doi":"10.1016/j.canlet.2025.217574","DOIUrl":"10.1016/j.canlet.2025.217574","url":null,"abstract":"<div><div>Breast cancer is one of the most prevalent cancers and has emerged as a major global challenge. Circulating tumor DNA (ctDNA), a liquid biopsy method, overcomes the accessibility limitations of tissue-based testing and is widely used for monitoring minimal residual disease and molecular relapse, predicting prognosis, evaluating the response of neoadjuvant therapy, and optimizing treatment decisions in non-metastatic breast cancer. However, the application of ctDNA still faces many challenges. Here, we survey the clinical applications of ctDNA in non-metastatic breast cancer and discuss the significant biological and technical challenges of utilizing ctDNA. Importantly, we investigate potential avenues for addressing the challenges. In addition, emerging technologies, including fragmentomics detection, methylation sequencing, and long-read sequencing, have clinical potential and could be a future direction. Proper utilization of machine learning facilitates the identification of meaningful patterns from complex fragment and methylation profiles of ctDNA. There is still a lack of clinical trials focused on the subsets of ctDNA (e.g., circulating mitochondrial DNA), ctDNA-inferred drug-resistant clonal evolution, tumor heterogeneity, and ctDNA-guided clinical decision-making in non-metastatic breast cancer. Due to regional differences in the number of registered clinical trials, it is essential to enhance communication and foster global collaboration to advance the field.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217574"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455014","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

Evaluation and preservation of fertility in patients with hematologic malignancies

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-19 DOI: 10.1016/j.canlet.2025.217569

Xiang Wang , Ruihao Huang , Lei Liu , Xiaoqi Wang , Xi Zhang

For patients with hematologic malignancies, novel therapeutic strategies offer the potential to achieve a complete clinical response and long-term survival. However, declining fertility has become a significant concern, impacting long-term quality of life. Conventional high-dose chemotherapy and radiotherapy are known to reduce fertility or cause sterility. Moreover, limited clinical data are available on the effects of newer therapies, such as targeted treatments and chimeric antigen receptor (CAR)-T cell therapy, on fertility. Additionally, there is no standard method for preserving fertility in these patients. Male patients can opt for sperm cryopreservation, whereas female patients may preserve fertility through embryo, oocyte, or ovarian tissue cryopreservation. However, preserving fertility in prepubescent patients remains particularly challenging. Therefore, hematologists must educate patients about the potential gonadal toxicity of cancer treatments and offer the most appropriate fertility preservation options.

引用次数: 0

SUMOylated hnRNPM suppresses PFKFB3 phosphorylation to regulate glycolysis and tumorigenesis SUMOylated hnRNPM 可抑制 PFKFB3 磷酸化，从而调节糖酵解和肿瘤发生。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-19 DOI: 10.1016/j.canlet.2025.217573

Ya-Xian Zhong , Huan-Bin Zhao , Meng-Han Lian , Jia-Ming Shen , Cheng-Xiao Li , Hong-Ming Ma , Dan Xu , Guo-Qiang Chen , Cheng Zhang

Heterogeneous nuclear ribonucleoprotein M (hnRNPM), a splicing regulatory factor with a majority of studies focused on its RNA-binding properties and effects on splicing outcome, is implicated in the progression of various kinds of human cancers, but its mechanisms remain largely enigmatic. Applying the global SUMOylated proteomic screening in colorectal cancer cells, herein we find that hnRNPM is SUMOylated at lysine 17 and Sentrin-specific protease 1 (SENP1) is essential for its de-SUMOylation. Although hnRNPM SUMOylation does not affect its known pre-mRNA splicing-related effects, more intriguingly, it remarkably influences lactate production. Mechanistically, SUMOylated hnRNPM interacts with 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) to affect its localization and inhibit its phosphorylation, thus suppressing glycolysis. Accordingly, SUMO-deficient hnRNPM promotes colorectal cancer cell proliferation and tumorigenesis in mice. Also, a negative correlation between hnRNPM SUMOylation and SENP1 expression or phosphorylated PFKFB3 levels can be found in CRC patient samples. These findings not only enhance our understanding of the multifaceted roles of hnRNPM in cancer biology but also open new avenues for the development of targeted therapies aimed at modulating hnRNPM SUMOylation.

{"title":"SUMOylated hnRNPM suppresses PFKFB3 phosphorylation to regulate glycolysis and tumorigenesis","authors":"Ya-Xian Zhong , Huan-Bin Zhao , Meng-Han Lian , Jia-Ming Shen , Cheng-Xiao Li , Hong-Ming Ma , Dan Xu , Guo-Qiang Chen , Cheng Zhang","doi":"10.1016/j.canlet.2025.217573","DOIUrl":"10.1016/j.canlet.2025.217573","url":null,"abstract":"<div><div>Heterogeneous nuclear ribonucleoprotein M (hnRNPM), a splicing regulatory factor with a majority of studies focused on its RNA-binding properties and effects on splicing outcome, is implicated in the progression of various kinds of human cancers, but its mechanisms remain largely enigmatic. Applying the global SUMOylated proteomic screening in colorectal cancer cells, herein we find that hnRNPM is SUMOylated at lysine 17 and Sentrin-specific protease 1 (SENP1) is essential for its de-SUMOylation. Although hnRNPM SUMOylation does not affect its known pre-mRNA splicing-related effects, more intriguingly, it remarkably influences lactate production. Mechanistically, SUMOylated hnRNPM interacts with 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) to affect its localization and inhibit its phosphorylation, thus suppressing glycolysis. Accordingly, SUMO-deficient hnRNPM promotes colorectal cancer cell proliferation and tumorigenesis in mice. Also, a negative correlation between hnRNPM SUMOylation and SENP1 expression or phosphorylated PFKFB3 levels can be found in CRC patient samples. These findings not only enhance our understanding of the multifaceted roles of hnRNPM in cancer biology but also open new avenues for the development of targeted therapies aimed at modulating hnRNPM SUMOylation.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217573"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472443","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

Extracellular vesicle biomarkers redefine prostate cancer radiotherapy

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-18 DOI: 10.1016/j.canlet.2025.217568

Hei Yeung Chan , Qi Wang , Andrew Howie , Joseph Bucci , Peter Graham , Yong Li

Radiotherapy (RT) remains a cornerstone in the treatment of prostate cancer (PCa). Extracellular vesicles (EVs), nano-sized particles secreted by cells, play important roles in intercellular communication within the tumour microenvironment (TME) and contribute to tumour growth, metastasis, and therapy resistance. Recent advancements demonstrate the potential of EVs as biomarkers for cancer diagnosis, prognosis, and treatment monitoring. Accumulating evidence supports the role of EVs in modulating RT outcomes by shaping the TME, mediating radioresistance, and influencing cancer metastasis. Despite substantial progress, challenges remain, including the heterogeneity of EV biogenesis, variability in cargo composition, and the absence of standardised methods for EV isolation and characterisation. While the therapeutic and diagnostic prospects of EVs in PCa management are promising, further research is needed to clarify the mechanisms through which EVs impact RT and to translate these findings into clinical practice. Incorporating EV research into PCa treatment paradigms could enhance diagnostic accuracy, enable real-time monitoring of RT responses, and support the development of new targeted therapeutic strategies. This review discusses recent progress in understanding EVs in the context of RT for PCa, focuses on their roles in modulating tumour growth, contributing to radioresistance within the TME, and facilitating the monitoring of RT efficacy and recurrence. In addition, the potential of EVs as biomarkers for liquid biopsy and their applications in enhancing radiosensitivity or overcoming radioresistance is also explored.

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引用次数: 0

Lactate drives senescence-resistant lineages in hepatocellular carcinoma via histone H2B lactylation of NDRG1

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-02-18 DOI: 10.1016/j.canlet.2025.217567

Lu Li , Jinyun Dong , Chunwei Xu , Shiqun Wang

Hepatocellular carcinoma (HCC) treatment options remain limited despite advances in targeted therapies for molecularly-defined cancers. To address tumor heterogeneity, we reconstructed HCC clonal evolution through single-cell RNA sequencing trajectory analysis, identifying 902 signature genes across seven cellular states. Weighted gene co-expression network analysis of public HCC datasets revealed tumor-grade-associated modules and established a 14-gene prognostic model linked to clonal evolution. Central to this model is the LDHA-NDRG1 axis - two hypoxia-responsive regulators showing coordinated spatiotemporal expression patterns during cancer progression. Dual-expressing cell lineages correlated with poor prognosis and senescence resistance through LDHA-mediated lactylation of histone H2B at K58 on NDRG1, an epigenetic mechanism connecting metabolic reprogramming to senescence evasion. Therapeutically, dual inhibition of this axis extended survival in metastatic HCC murine models. Our findings reveal that lactate-driven epigenetic modification via the LDHA-NDRG1 axis creates a molecularly distinct subpopulation enabling senescence resistance, providing mechanistic insights into HCC heterogeneity. This work proposes a precision medicine strategy targeting lactylation-mediated epigenetic regulation, with implications for developing combination therapies and patient stratification based on clonal evolution patterns.

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