Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101120
Zhigang Huang , Bin Liu , Xiaoju Li , Chenghua Jin , Quansen Hu , Zhiwei Zhao , Yimin Sun , Qian Wang
Bladder cancer is a prevalent malignancy within the urinary system. Prior research has suggested that glutamine metabolism plays a crucial role in driving bladder cancer progression. However, the precise molecular mechanism governing glutamine metabolism in bladder cancer is still inadequately understood. The research revealed a significant correlation between high levels of RUNX2 and SLC7A6 and advanced clinical stage, as well as poor prognosis, in bladder cancer patients. Furthermore, manipulating the levels of RUNX2 through overexpression or silencing demonstrated a significant impact on glutamine and bladder cancer progression. Mechanically, RUNX2 regulates the transcription of SLC7A6, resulting in enhanced glutamine metabolism and promoting the progression of bladder cancer. Overall, this research affirms the crucial function of RUNX2 as a key transcription factor to promoting glutamine and cancer development through modulation of SLC7A6. Targeting RUNX2 could represent a promising therapeutic approach for addressing aberrant glutamine metabolism in bladder cancer.
{"title":"RUNX2 enhances bladder cancer progression by promoting glutamine metabolism","authors":"Zhigang Huang , Bin Liu , Xiaoju Li , Chenghua Jin , Quansen Hu , Zhiwei Zhao , Yimin Sun , Qian Wang","doi":"10.1016/j.neo.2024.101120","DOIUrl":"10.1016/j.neo.2024.101120","url":null,"abstract":"<div><div>Bladder cancer is a prevalent malignancy within the urinary system. Prior research has suggested that glutamine metabolism plays a crucial role in driving bladder cancer progression. However, the precise molecular mechanism governing glutamine metabolism in bladder cancer is still inadequately understood. The research revealed a significant correlation between high levels of RUNX2 and SLC7A6 and advanced clinical stage, as well as poor prognosis, in bladder cancer patients. Furthermore, manipulating the levels of RUNX2 through overexpression or silencing demonstrated a significant impact on glutamine and bladder cancer progression. Mechanically, RUNX2 regulates the transcription of SLC7A6, resulting in enhanced glutamine metabolism and promoting the progression of bladder cancer. Overall, this research affirms the crucial function of RUNX2 as a key transcription factor to promoting glutamine and cancer development through modulation of SLC7A6. Targeting RUNX2 could represent a promising therapeutic approach for addressing aberrant glutamine metabolism in bladder cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101120"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leptomeningeal metastasis (LM) is a challenging complication of non-small cell lung cancer (NSCLC). Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis using next-generation sequencing (NGS) offers insights into resistance mechanisms and potential treatment strategies. We conducted a study from February 2022 to April 2023 involving patients from five hospitals in Taiwan who had recurrent or advanced NSCLC with LM. These patients underwent CSF cfDNA analysis using a 118-gene targeted panel for NGS, with comprehensive clinical data collected. Among 25 enrolled patients, 22 (88.0 %) had EGFR mutations, while three (12.0 %) had EML4-ALK fusion, KIF5B-RET fusion, and ERBB2 A775_G776insSVMA. CSF cfDNA sequencing of 27 samples (from 25 patients) all confirmed their original driver mutations. Of total cohort, 18 patients (72.0 %) underwent intrathecal pemetrexed (ITP), with a median survival time of 7.4 months (95.0 % confidence interval, 3.3–11.6) from the initiation of ITP to death. Among them, ten individuals (55.6 %) survived beyond 6 months. Notably, MET copy number gain (CNG) correlated significantly with survival time exceeding 6 months after ITP (p = 0.007). The coexistence of EGFR T790M and EGFR-independent resistance alterations was associated with shorter survival times after ITP, with a median survival time of 1.9 months compared to 9.9 months for those without EGFR T790M (p = 0.010). Our results highlight CSF cfDNA NGS's potential in LM resistance understanding and ITP efficacy prediction. MET CNG positively impacts survival for ITP recipients, whereas the coexistence of EGFR T790M and EGFR-independent resistance mechanisms leads to poor outcomes.
{"title":"Clinical utility and predictive value of cerebrospinal fluid cell-free DNA profiling in non-small cell lung cancer patients with leptomeningeal metastasis","authors":"Sheng-Kai Liang , Wei-Yu Liao , Jin-Yuan Shih , Chia-Lin Hsu , Ching-Yao Yang , Shang-Gin Wu , Yen-Ting Lin , Yueh-Feng Wen , Lun-Che Chen , Yen-Fu Chen , Ya-Fang Chen , Yen-Heng Lin , Chong-Jen Yu","doi":"10.1016/j.neo.2024.101113","DOIUrl":"10.1016/j.neo.2024.101113","url":null,"abstract":"<div><div>Leptomeningeal metastasis (LM) is a challenging complication of non-small cell lung cancer (NSCLC). Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis using next-generation sequencing (NGS) offers insights into resistance mechanisms and potential treatment strategies. We conducted a study from February 2022 to April 2023 involving patients from five hospitals in Taiwan who had recurrent or advanced NSCLC with LM. These patients underwent CSF cfDNA analysis using a 118-gene targeted panel for NGS, with comprehensive clinical data collected. Among 25 enrolled patients, 22 (88.0 %) had <em>EGFR</em> mutations, while three (12.0 %) had <em>EML4-ALK</em> fusion, <em>KIF5B-RET</em> fusion, and <em>ERBB2</em> A775_G776insSVMA. CSF cfDNA sequencing of 27 samples (from 25 patients) all confirmed their original driver mutations. Of total cohort, 18 patients (72.0 %) underwent intrathecal pemetrexed (ITP), with a median survival time of 7.4 months (95.0 % confidence interval, 3.3–11.6) from the initiation of ITP to death. Among them, ten individuals (55.6 %) survived beyond 6 months. Notably, <em>MET</em> copy number gain (CNG) correlated significantly with survival time exceeding 6 months after ITP (<em>p</em> = 0.007). The coexistence of <em>EGFR</em> T790M and EGFR-independent resistance alterations was associated with shorter survival times after ITP, with a median survival time of 1.9 months compared to 9.9 months for those without <em>EGFR</em> T790M (<em>p</em> = 0.010). Our results highlight CSF cfDNA NGS's potential in LM resistance understanding and ITP efficacy prediction. <em>MET</em> CNG positively impacts survival for ITP recipients, whereas the coexistence <em>of EGFR</em> T790M and EGFR-independent resistance mechanisms leads to poor outcomes.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101113"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We investigated the mechanisms of interaction between bladder cancer (BC) cells and tumor-associated macrophages (TAMs). Coculturing BC cell lines (UMUC3 and T24) with macrophage-like cells differentiated from THP-1 into M2-like TAMs revealed a decrease in Cluster of Differentiation (CD) 68 expression and an increase in CD206 expression. This differentiation enhanced BC cell migration and invasion. Additionally, M2-like TAMs significantly increased the secretion of C–C motif chemokine ligand (CCL) 20, which promotes BC cell migration and invasion via the MEK/ERK signaling pathway through its paracrine effects. Coculturing with TAMs also elevated the expression of CC chemokine receptor (CCR) 6 in BC cells, indicating increased sensitivity to CCL20. Immunohistochemistry analysis of human BC tissues showed a significant correlation between CCR6 expression levels and BC prognosis. Inhibition of CCR6 reduced BC cell metastasis both in vitro and in vivo. Additionally, CXCL1 secretion from BC cells was found to contribute to the M2-like polarization of macrophages and to enhance BC cell migration and invasion through autocrine and indirect effects. In summary, CCL20 and CXCL1 play crucial roles in the interaction between BC cells and TAMs.
{"title":"Tumor-associated macrophages promote bladder cancer metastasis through the CCL20-CCR6 axis","authors":"Ryunosuke Nakagawa , Kouji Izumi , Kaoru Hiratsuka , Takahiro Inaba , Yoshiki Koketsu , Ren Toriumi , Shuhei Aoyama , Taiki Kamijima , Hiroshi Kano , Tomoyuki Makino , Renato Naito , Suguru Kadomoto , Hiroaki Iwamoto , Hiroshi Yaegashi , Shohei Kawaguchi , Takahiro Nohara , Kazuyoshi Shigehara , Hiroki Nakata , Wen-Jye Lin , Atsushi Mizokami","doi":"10.1016/j.neo.2024.101103","DOIUrl":"10.1016/j.neo.2024.101103","url":null,"abstract":"<div><div>We investigated the mechanisms of interaction between bladder cancer (BC) cells and tumor-associated macrophages (TAMs). Coculturing BC cell lines (UMUC3 and T24) with macrophage-like cells differentiated from THP-1 into M2-like TAMs revealed a decrease in Cluster of Differentiation (CD) 68 expression and an increase in CD206 expression. This differentiation enhanced BC cell migration and invasion. Additionally, M2-like TAMs significantly increased the secretion of C–C motif chemokine ligand (CCL) 20, which promotes BC cell migration and invasion via the MEK/ERK signaling pathway through its paracrine effects. Coculturing with TAMs also elevated the expression of CC chemokine receptor (CCR) 6 in BC cells, indicating increased sensitivity to CCL20. Immunohistochemistry analysis of human BC tissues showed a significant correlation between CCR6 expression levels and BC prognosis. Inhibition of CCR6 reduced BC cell metastasis both in vitro and in vivo. Additionally, CXCL1 secretion from BC cells was found to contribute to the M2-like polarization of macrophages and to enhance BC cell migration and invasion through autocrine and indirect effects. In summary, CCL20 and CXCL1 play crucial roles in the interaction between BC cells and TAMs.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101103"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101102
Wensun Chen , Siqi Wu , Yifan Chen , Weijian Li , Yiqing Cao , Yingchun Liang , Xiyu Dai , Xinan Chen , Yilin Chen , Tian Chen , Shenghua Liu , Chen Yang , Haowen Jiang
Yes-associated protein 1 (YAP1) has attracted attention for its potential in the treatment of various types of malignancies. The Hippo-YAP1 axis is inhibited in bladder cancer (BC), which is a major driver of BC progression and oncogenesis. Hippo pathway activity is controlled by the phosphorylation cascade in the MST1/2-LATS1/2-YAP1 axis, in addition to other modifications such as ubiquitination of the Hippo pathway proteins through the co-regulation of E3 ligases and deubiquitinases. In this study, we identified USP20 as a Hippo/YAP1 pathway-related deubiquitinase using combined siRNA screening and a deubiquitinase overexpression assay. Further analysis revealed that USP20 directly regulated the expression of YAP1 and its downstream target genes connective tissue growth factor and cysteine-rich angiogenic inducer 61. A tissue microarray assay confirmed that USP20 expression was elevated in tumor tissues and correlated with YAP1 expression. Analysis of the underlying mechanisms revealed that USP20 directly interacted with the YAP1 protein and promoted its stability through inhibition of K48-linked poly-ubiquitination. Our findings revealed that USP20 serves as a deubiquitinase and regulates the Hippo-YAP1 pathway in BC.
{"title":"USP20 mediates malignant phenotypic changes in bladder cancer through direct interactions with YAP1","authors":"Wensun Chen , Siqi Wu , Yifan Chen , Weijian Li , Yiqing Cao , Yingchun Liang , Xiyu Dai , Xinan Chen , Yilin Chen , Tian Chen , Shenghua Liu , Chen Yang , Haowen Jiang","doi":"10.1016/j.neo.2024.101102","DOIUrl":"10.1016/j.neo.2024.101102","url":null,"abstract":"<div><div>Yes-associated protein 1 (YAP1) has attracted attention for its potential in the treatment of various types of malignancies. The Hippo-YAP1 axis is inhibited in bladder cancer (BC), which is a major driver of BC progression and oncogenesis. Hippo pathway activity is controlled by the phosphorylation cascade in the MST1/2-LATS1/2-YAP1 axis, in addition to other modifications such as ubiquitination of the Hippo pathway proteins through the co-regulation of E3 ligases and deubiquitinases. In this study, we identified USP20 as a Hippo/YAP1 pathway-related deubiquitinase using combined siRNA screening and a deubiquitinase overexpression assay. Further analysis revealed that USP20 directly regulated the expression of YAP1 and its downstream target genes connective tissue growth factor and cysteine-rich angiogenic inducer 61. A tissue microarray assay confirmed that USP20 expression was elevated in tumor tissues and correlated with YAP1 expression. Analysis of the underlying mechanisms revealed that USP20 directly interacted with the YAP1 protein and promoted its stability through inhibition of K48-linked poly-ubiquitination. Our findings revealed that USP20 serves as a deubiquitinase and regulates the Hippo-YAP1 pathway in BC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101102"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.100964
Seema Chugh , Jean C. Tien , Jennifer Hon , Carson Kenum , Rahul Mannan , Yunhui Cheng , Chi Chiang Li , Zainab I. Taher , Andrew D. Delekta , Pushpinder Singh Bawa , Ingrid J. Apel , Stephanie J. Miner , Xuhong Cao , Rohit Mehra , Saravana M. Dhanasekaran , Yuanyuan Qiao , Rajen Mody , Arul M. Chinnaiyan
Neuroblastoma (NB) is a predominantly pediatric cancer with greater than 90% of cases arising in children under the age of five. More than half of patients have metastases detected at diagnosis, and high-risk disease is associated with five-year survival rates of only 50–60 %. Standard therapy involves highly toxic chemotherapy, surgery, radiation, and immunotherapy, and less toxic, more specific targeted therapies are urgently needed. Genomic studies have identified common driver aberrations in high-risk NB, such as MYCN amplification. In addition, a proportion of high-risk patients harbor amplification or activating mutations in anaplastic lymphoma kinase (ALK), and co-occurrence of ALK mutations and MYCN amplification have been associated with aggressive disease. In this study, we analyzed the efficacy of a Phase Ia-cleared, orally bioavailable dual ALK and focal adhesion kinase (FAK) inhibitor, ESK440, in multiple preclinical NB models. ESK440 potently inhibited proliferation of NB cell lines, with increased sensitivity in cell lines harboring ALK aberrations. ALK, FAK, and downstream target activation were rapidly decreased upon ESK440 treatment, and this was associated with impaired cellular migration and invasion. Importantly, ESK440 treatment also decreased MYCN levels. NB cell line and patient-derived xenograft studies showed significant reduction in tumor growth in ESK440-treated mice with no signs of toxicity. In certain NB models, ESK440 showed comparable or enhanced efficacy to lorlatinib, another clinical ALK inhibitor, and a lorlatinib-resistant cell line (COG-N-561 LR) retained sensitivity to ESK440. These preclinical results indicate that ESK440 is a promising targeted agent for ALK-driven NB and support future clinical studies to evaluate its efficacy in NB patients.
神经母细胞瘤（NB）主要是一种儿童癌症，90%以上的病例发生在五岁以下的儿童身上。一半以上的患者在确诊时已发现转移，高危疾病的五年生存率仅为 50%-60%。标准疗法包括高毒性化疗、手术、放疗和免疫疗法，目前急需毒性较低、更具特异性的靶向疗法。基因组研究发现了高危 NB 中常见的驱动基因畸变，如 MYCN 扩增。此外，一部分高危患者存在无性淋巴瘤激酶（ALK）扩增或激活突变，ALK突变和MYCN扩增的同时存在与侵袭性疾病有关。在这项研究中，我们在多个临床前 NB 模型中分析了一种 Ia 期通过的口服生物可用性 ALK 和局灶粘附激酶（FAK）双重抑制剂 ESK440 的疗效。ESK440 能有效抑制 NB 细胞系的增殖，对携带 ALK 畸变的细胞系的敏感性更高。ESK440治疗后，ALK、FAK和下游靶点活化迅速降低，这与细胞迁移和侵袭受损有关。重要的是，ESK440还能降低MYCN水平。NB细胞系和患者衍生异种移植研究显示，ESK440治疗小鼠的肿瘤生长显著减少，且无毒性迹象。在某些 NB 模型中，ESK440 显示出与另一种临床 ALK 抑制剂洛拉替尼（lorlatinib）相当或更强的疗效，而且洛拉替尼耐药细胞系（COG-N-561 LR）对 ESK440 仍保持敏感性。这些临床前研究结果表明，ESK440是一种治疗ALK驱动的NB的有前景的靶向药物，并支持未来评估其在NB患者中疗效的临床研究。
{"title":"Therapeutic benefit of the dual ALK/FAK inhibitor ESK440 in ALK-driven neuroblastoma","authors":"Seema Chugh , Jean C. Tien , Jennifer Hon , Carson Kenum , Rahul Mannan , Yunhui Cheng , Chi Chiang Li , Zainab I. Taher , Andrew D. Delekta , Pushpinder Singh Bawa , Ingrid J. Apel , Stephanie J. Miner , Xuhong Cao , Rohit Mehra , Saravana M. Dhanasekaran , Yuanyuan Qiao , Rajen Mody , Arul M. Chinnaiyan","doi":"10.1016/j.neo.2024.100964","DOIUrl":"10.1016/j.neo.2024.100964","url":null,"abstract":"<div><div>Neuroblastoma (NB) is a predominantly pediatric cancer with greater than 90% of cases arising in children under the age of five. More than half of patients have metastases detected at diagnosis, and high-risk disease is associated with five-year survival rates of only 50–60 %. Standard therapy involves highly toxic chemotherapy, surgery, radiation, and immunotherapy, and less toxic, more specific targeted therapies are urgently needed. Genomic studies have identified common driver aberrations in high-risk NB, such as <em>MYCN</em> amplification. In addition, a proportion of high-risk patients harbor amplification or activating mutations in anaplastic lymphoma kinase (<em>ALK</em>), and co-occurrence of <em>ALK</em> mutations and <em>MYCN</em> amplification have been associated with aggressive disease. In this study, we analyzed the efficacy of a Phase Ia-cleared, orally bioavailable dual ALK and focal adhesion kinase (FAK) inhibitor, ESK440, in multiple preclinical NB models. ESK440 potently inhibited proliferation of NB cell lines, with increased sensitivity in cell lines harboring <em>ALK</em> aberrations. ALK, FAK, and downstream target activation were rapidly decreased upon ESK440 treatment, and this was associated with impaired cellular migration and invasion. Importantly, ESK440 treatment also decreased MYCN levels. NB cell line and patient-derived xenograft studies showed significant reduction in tumor growth in ESK440-treated mice with no signs of toxicity. In certain NB models, ESK440 showed comparable or enhanced efficacy to lorlatinib, another clinical ALK inhibitor, and a lorlatinib-resistant cell line (COG-N-561 LR) retained sensitivity to ESK440. These preclinical results indicate that ESK440 is a promising targeted agent for ALK-driven NB and support future clinical studies to evaluate its efficacy in NB patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 100964"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139374349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101106
Marta Avinent-Pérez , Frank Westermann , Samuel Navarro , Amparo López-Carrasco , Rosa Noguera
Background
The heterogeneous prognosis in neuroblastoma, shaped by telomere maintenance mechanisms (TMMs), notably the alternative lengthening of telomeres (ALT) pathway, necessitates a refined risk classification for high-risk patients. Current systems often lack precision, hindering tailored treatment approaches. This individual participant data (IPD) meta-analysis of survival among ALT-positive patients aims to improve risk classification systems, enhancing therapeutic strategies and patient outcomes.
Methods
Following PRISMA-IPD guidelines, we conducted a comprehensive review of neuroblastoma patients retrieved from PubMed, Scopus, and Embase databases until March-2024. Patients were stratified into ALT-positive and TMM-negative subgroups. Overall and event-free survival probabilities were evaluated.
Results
In our cohort of 293 patients (156 ALT-positive, 137 TMM-negative) obtained from eight different studies, ALT-positive individuals displayed lower survival rates than TMM-negative patients. Non-stage 4 ALT-positive patients had reduced overall and event-free survival probabilities compared to their TMM-negative counterparts, indicating potential misclassification. Stage 4 ALT-positive patients similarly showed poorer survival outcomes than non-stage 4 TMM-negative patients, underscoring the significance of ALT in patient prognosis.
Conclusions
Our study highlights poorer outcomes in ALT-positive neuroblastoma patients, emphasizing the need to integrate TMM status into international risk classification guidelines. Standardizing TMM assessment is key for refining treatment strategies, considering the unique biology of ALT-positive patients.
{"title":"Tackling ALT-positive neuroblastoma: is it time to redefine risk classification systems? A systematic review with IPD meta-analysis","authors":"Marta Avinent-Pérez , Frank Westermann , Samuel Navarro , Amparo López-Carrasco , Rosa Noguera","doi":"10.1016/j.neo.2024.101106","DOIUrl":"10.1016/j.neo.2024.101106","url":null,"abstract":"<div><h3>Background</h3><div>The heterogeneous prognosis in neuroblastoma, shaped by telomere maintenance mechanisms (TMMs), notably the alternative lengthening of telomeres (ALT) pathway, necessitates a refined risk classification for high-risk patients. Current systems often lack precision, hindering tailored treatment approaches. This individual participant data (IPD) meta-analysis of survival among ALT-positive patients aims to improve risk classification systems, enhancing therapeutic strategies and patient outcomes.</div></div><div><h3>Methods</h3><div>Following PRISMA-IPD guidelines, we conducted a comprehensive review of neuroblastoma patients retrieved from PubMed, Scopus, and Embase databases until March-2024. Patients were stratified into ALT-positive and TMM-negative subgroups. Overall and event-free survival probabilities were evaluated.</div></div><div><h3>Results</h3><div>In our cohort of 293 patients (156 ALT-positive, 137 TMM-negative) obtained from eight different studies, ALT-positive individuals displayed lower survival rates than TMM-negative patients. Non-stage 4 ALT-positive patients had reduced overall and event-free survival probabilities compared to their TMM-negative counterparts, indicating potential misclassification. Stage 4 ALT-positive patients similarly showed poorer survival outcomes than non-stage 4 TMM-negative patients, underscoring the significance of ALT in patient prognosis.</div></div><div><h3>Conclusions</h3><div>Our study highlights poorer outcomes in ALT-positive neuroblastoma patients, emphasizing the need to integrate TMM status into international risk classification guidelines. Standardizing TMM assessment is key for refining treatment strategies, considering the unique biology of ALT-positive patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101106"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101108
Jeannette C. Oosterwijk-Wakka , Liesbeth Houkes , Loes F.M. van der Zanden , Lambertus A.L.M. Kiemeney , Kerstin Junker , Anne Y Warren , Tim Eisen , Ulrich Jaehde , Marius T Radu , Rob Ruijtenbeek , Egbert Oosterwijk
Introduction
Treatment with Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor (TKI) has increased the progression-free survival (PFS) and overall-survival (OS) of patients with metastasized renal cell carcinoma (mRCC). With modest OS improvement and variable response and toxicity predictive and/or prognostic biomarkers are needed to personalize patient management: Prediction of individual TKI therapy response and resistance will increase successful treatment outcome while reducing unnecessary drug use and expense. The aim of this study was to investigate whether kinase activity analysis can predict sunitinib response and/or toxicity using tissue samples obtained from primary clear cell RCC (ccRCC) from a cohort of clinically annotated patients with mRCC receiving sunitinib as first-line treatment.
Materials and Methods
EuroTARGET partners collected ccRCC and matched normal kidney tissue samples immediately after surgery, snap-frozen and stored at -80°C until use. Phosphotyrosine-activity profiling was performed using PamChip® peptide microarrays (144 peptides derived from known phosphorylation sites in Protein Tyrosine Kinase substrates) of lysed tissue samples (5 µg protein input) of 163 mRCC patients. Evolve software Was used to analyze kinome profiles and Bionavigator was used for unsupervised and supervised clustering. The kinexus kinase predictor (www.phosphonet.ca) was used to analyze the peptide lists within the clusters.
Results
Kinome data was available from 94 patients who received sunitinib as 1st-line treatment and had complete follow-up of their clinical data (PFS, OS and toxicity) for at least 6 months. Matched normal tissue was available from 14 mRCC patients. Supervised clustering of basal kinome activity could correctly classify mRCC patients with PFS >9 months versus PFS<9 months with an accuracy of 61 %. Unsupervised hierarchical clustering revealed 3 major clusters related to immune signaling, VEGF pathway, and immune signaling/cell adhesion. Basal kinase activity levels of patients with short PFS were substantially higher compared to patients who experienced extended PFS.
Discussion/Conclusion
Based on kinase levels ccRCC tumors can be subdivided into 3 clusters which may reflect the aggressiveness of these tumors. The accuracy of response prediction of 61 % based on basal kinase levels is too low to justify implementation. STK assays may help to predict sunitinib toxicity and guide clinical management. Additionally, it is possible that mRCC patients with an immune kinase signature are better checkpoint inhibitor candidates, but this needs to be studied.
{"title":"Kinomic profiling to predict sunitinib response of patients with metastasized clear cell Renal Cell Carcinoma","authors":"Jeannette C. Oosterwijk-Wakka , Liesbeth Houkes , Loes F.M. van der Zanden , Lambertus A.L.M. Kiemeney , Kerstin Junker , Anne Y Warren , Tim Eisen , Ulrich Jaehde , Marius T Radu , Rob Ruijtenbeek , Egbert Oosterwijk","doi":"10.1016/j.neo.2024.101108","DOIUrl":"10.1016/j.neo.2024.101108","url":null,"abstract":"<div><h3>Introduction</h3><div>Treatment with Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor (TKI) has increased the progression-free survival (PFS) and overall-survival (OS) of patients with metastasized renal cell carcinoma (mRCC). With modest OS improvement and variable response and toxicity predictive and/or prognostic biomarkers are needed to personalize patient management: Prediction of individual TKI therapy response and resistance will increase successful treatment outcome while reducing unnecessary drug use and expense. The aim of this study was to investigate whether kinase activity analysis can predict sunitinib response and/or toxicity using tissue samples obtained from primary clear cell RCC (ccRCC) from a cohort of clinically annotated patients with mRCC receiving sunitinib as first-line treatment.</div></div><div><h3>Materials and Methods</h3><div>EuroTARGET partners collected ccRCC and matched normal kidney tissue samples immediately after surgery, snap-frozen and stored at -80°C until use. Phosphotyrosine-activity profiling was performed using PamChip® peptide microarrays (144 peptides derived from known phosphorylation sites in Protein Tyrosine Kinase substrates) of lysed tissue samples (5 µg protein input) of 163 mRCC patients. Evolve software Was used to analyze kinome profiles and Bionavigator was used for unsupervised and supervised clustering. The kinexus kinase predictor (<span><span>www.phosphonet.ca</span><svg><path></path></svg></span>) was used to analyze the peptide lists within the clusters.</div></div><div><h3>Results</h3><div>Kinome data was available from 94 patients who received sunitinib as 1st-line treatment and had complete follow-up of their clinical data (PFS, OS and toxicity) for at least 6 months. Matched normal tissue was available from 14 mRCC patients. Supervised clustering of basal kinome activity could correctly classify mRCC patients with PFS >9 months <em>versus</em> PFS<9 months with an accuracy of 61 %. Unsupervised hierarchical clustering revealed 3 major clusters related to immune signaling, VEGF pathway, and immune signaling/cell adhesion. Basal kinase activity levels of patients with short PFS were substantially higher compared to patients who experienced extended PFS.</div></div><div><h3>Discussion/Conclusion</h3><div>Based on kinase levels ccRCC tumors can be subdivided into 3 clusters which may reflect the aggressiveness of these tumors. The accuracy of response prediction of 61 % based on basal kinase levels is too low to justify implementation. STK assays may help to predict sunitinib toxicity and guide clinical management. Additionally, it is possible that mRCC patients with an immune kinase signature are better checkpoint inhibitor candidates, but this needs to be studied.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101108"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101118
Yining Zhang , Zhenfang Li , Chengchi Zhang , Chengying Shao , Yanting Duan , Guowan Zheng , Yu Cai , Minghua Ge , Jiajie Xu
Head and neck squamous cell carcinoma (HNSCC) are the most common type of head and neck tumor that severely threatens human health due to its highly aggressive nature and susceptibility to distant metastasis. The diagnosis of HNSCC currently relies on biopsy and histopathological examination of suspicious lesions. However, the early mucosal changes are subtle and difficult to detect by conventional oral examination. As for treatment, surgery is still the primary treatment modality. Due to the complex anatomy and the lack of intraoperative modalities to accurately determine the incision margins, surgeons are in a dilemma between extensive tumor removal and improving the quality of patient survival. As more knowledge is gained about HNSCC, the increasing recognition of the value of optical imaging has been emphasized. Optical technology offers distinctive possibilities for early preoperative diagnosis, intraoperative real-time visualization of tumor margins, sentinel lymph node biopsies, phototherapy. Fluorescence imaging, narrow-band imaging, Raman spectroscopy, optical coherence tomography, hyperspectral imaging, and photoacoustic imaging have been reported for imaging HNSCC. This article provides a comprehensive overview of the fundamental principles and clinical applications of optical imaging in the diagnosis and treatment of HNSCC, focusing on identifying its strengths and limitations to facilitate advancements in this field.
{"title":"Recent advances of photodiagnosis and treatment for head and neck squamous cell carcinoma","authors":"Yining Zhang , Zhenfang Li , Chengchi Zhang , Chengying Shao , Yanting Duan , Guowan Zheng , Yu Cai , Minghua Ge , Jiajie Xu","doi":"10.1016/j.neo.2024.101118","DOIUrl":"10.1016/j.neo.2024.101118","url":null,"abstract":"<div><div>Head and neck squamous cell carcinoma (HNSCC) are the most common type of head and neck tumor that severely threatens human health due to its highly aggressive nature and susceptibility to distant metastasis. The diagnosis of HNSCC currently relies on biopsy and histopathological examination of suspicious lesions. However, the early mucosal changes are subtle and difficult to detect by conventional oral examination. As for treatment, surgery is still the primary treatment modality. Due to the complex anatomy and the lack of intraoperative modalities to accurately determine the incision margins, surgeons are in a dilemma between extensive tumor removal and improving the quality of patient survival. As more knowledge is gained about HNSCC, the increasing recognition of the value of optical imaging has been emphasized. Optical technology offers distinctive possibilities for early preoperative diagnosis, intraoperative real-time visualization of tumor margins, sentinel lymph node biopsies, phototherapy. Fluorescence imaging, narrow-band imaging, Raman spectroscopy, optical coherence tomography, hyperspectral imaging, and photoacoustic imaging have been reported for imaging HNSCC. This article provides a comprehensive overview of the fundamental principles and clinical applications of optical imaging in the diagnosis and treatment of HNSCC, focusing on identifying its strengths and limitations to facilitate advancements in this field.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101118"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive nature and dismal prognosis, largely attributed to its unique tumor microenvironment. However, the molecular mechanisms by which tumor-associated macrophages (TAMs) promote PDAC progression, particularly the role of β-catenin signaling in regulating TAM phenotype and function, remain incompletely understood.
Initially, we performed comprehensive analyses of RNA-seq and single-cell RNA-seq (scRNA-seq) datasets to investigate OSM and LOXL2 expression patterns in PDAC. Subsequently, the regulatory relationship between β-catenin and OSM in TAMs was examined using THP-1-derived macrophages. Furthermore, the functional impact of TAM-derived OSM on PDAC progression was evaluated through in vitro co-culture systems and an in vivo Panc02 lung metastasis model. Additionally, mechanistic studies employed pharmacological inhibitors and genetic approaches targeting β-catenin, OSM, and STAT3 signaling.
Notably, elevated expression of OSM and LOXL2 in PDAC specimens significantly correlated with poor patient survival. Intriguingly, scRNA-seq analysis revealed that β-catenin signaling was uniquely activated in TAMs among immune cells, which consequently regulated both TAM polarization and OSM expression. These OSM-expressing TAMs exhibited a distinct hybrid M1/M2 phenotype. Besides, our transcriptional profiling of TAMs revealed concurrent activation of both pro- and anti-inflammatory programs, with enrichment in Wnt signaling pathways. RNA-seq analysis of PDAC cells exposed to TAM-derived factors demonstrated enhanced mesenchymal transition and stemness properties, with direct enrichment of OSM signaling and extracellular matrix remodeling pathways. Mechanistically, β-catenin activation directly regulated both TAM phenotype and OSM expression, while TAM-conditioned medium enhanced PDAC cell migration, invasion, and lung metastasis. Importantly, inhibition of β-catenin signaling simultaneously altered TAM polarization and reduced OSM expression, which substantially attenuated epithelial-mesenchymal transition (EMT) in co-cultured PDAC cells. Moreover, STAT3 inhibition abolished OSM-induced LOXL2 expression and subsequent EMT programming.
Collectively, we identified a novel β-catenin/OSM-STAT3/LOXL2 signaling axis mediating TAM-induced PDAC progression. This pathway not only elucidates a previously unrecognized mechanism of β-catenin-mediated regulation of TAM function and phenotype but also presents potential therapeutic targets for intervention.
{"title":"β-Catenin mediated TAM phenotype promotes pancreatic cancer metastasis via the OSM/STAT3/LOXL2 axis","authors":"Yijia Zhang , Xinya Zhu , Liyuan Chen , Tianyu Gao , Guang Chen , Jin Zhu , Guoyu Wang , Daiying Zuo","doi":"10.1016/j.neo.2024.101096","DOIUrl":"10.1016/j.neo.2024.101096","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive nature and dismal prognosis, largely attributed to its unique tumor microenvironment. However, the molecular mechanisms by which tumor-associated macrophages (TAMs) promote PDAC progression, particularly the role of β-catenin signaling in regulating TAM phenotype and function, remain incompletely understood.</div><div>Initially, we performed comprehensive analyses of RNA-seq and single-cell RNA-seq (scRNA-seq) datasets to investigate OSM and LOXL2 expression patterns in PDAC. Subsequently, the regulatory relationship between β-catenin and OSM in TAMs was examined using THP-1-derived macrophages. Furthermore, the functional impact of TAM-derived OSM on PDAC progression was evaluated through <em>in vitro</em> co-culture systems and an <em>in vivo</em> Panc02 lung metastasis model. Additionally, mechanistic studies employed pharmacological inhibitors and genetic approaches targeting β-catenin, OSM, and STAT3 signaling.</div><div>Notably, elevated expression of OSM and LOXL2 in PDAC specimens significantly correlated with poor patient survival. Intriguingly, scRNA-seq analysis revealed that β-catenin signaling was uniquely activated in TAMs among immune cells, which consequently regulated both TAM polarization and OSM expression. These OSM-expressing TAMs exhibited a distinct hybrid M1/M2 phenotype. Besides, our transcriptional profiling of TAMs revealed concurrent activation of both pro- and anti-inflammatory programs, with enrichment in Wnt signaling pathways. RNA-seq analysis of PDAC cells exposed to TAM-derived factors demonstrated enhanced mesenchymal transition and stemness properties, with direct enrichment of OSM signaling and extracellular matrix remodeling pathways. Mechanistically, β-catenin activation directly regulated both TAM phenotype and OSM expression, while TAM-conditioned medium enhanced PDAC cell migration, invasion, and lung metastasis. Importantly, inhibition of β-catenin signaling simultaneously altered TAM polarization and reduced OSM expression, which substantially attenuated epithelial-mesenchymal transition (EMT) in co-cultured PDAC cells. Moreover, STAT3 inhibition abolished OSM-induced LOXL2 expression and subsequent EMT programming.</div><div>Collectively, we identified a novel β-catenin/OSM-STAT3/LOXL2 signaling axis mediating TAM-induced PDAC progression. This pathway not only elucidates a previously unrecognized mechanism of β-catenin-mediated regulation of TAM function and phenotype but also presents potential therapeutic targets for intervention.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101096"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101109
Xumin Zhou , Shilong Cheng , Zhongjie Chen , Jinming Zhang , Jiaqi Wang , Qiang Li , Xumin Zhou
Immunotherapy with checkpoint inhibitors produced significant clinical responses in a subset of cancer patients who were resistant to prior therapies. However, Castration-resistant prostate cancer (CRPC) is seriously lack of T cell infiltration, which greatly limits the clinical application of immunotherapy, but the mechanism is unclear. In the present study, in silico analyses and experimental data show that HnRNP L was significantly negatively correlated with CD4+ and CD8+ T cells infiltration in patients; besides, we found deficiency of HnRNP L recruites CD4+ and CD8+ T cells infiltration and impairs tumorigenesis. Mechanically, HnRNP L enhanced the translation of c-Myc and then promoted CXCL8 secretion via alternative splicing of EIF4G1. In vivo, inhibition of EIF4G1 by the inhibitor, SBI-0640756, attenuated HnRNP l-induced tumor progression and immunosuppressive activity. And most of all, therapeutic synergy between HnRNP L knockdown and Anti-PD-1 could significantly suppress xenograft prostate cancer growth. In summary, this study revealled the molecular mechanism of HnRNP L regulating the immune infiltration, which provides a new theoretical basis for overcoming the limitation of immunotherapy for CRPC.
{"title":"Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer","authors":"Xumin Zhou , Shilong Cheng , Zhongjie Chen , Jinming Zhang , Jiaqi Wang , Qiang Li , Xumin Zhou","doi":"10.1016/j.neo.2024.101109","DOIUrl":"10.1016/j.neo.2024.101109","url":null,"abstract":"<div><div>Immunotherapy with checkpoint inhibitors produced significant clinical responses in a subset of cancer patients who were resistant to prior therapies. However, Castration-resistant prostate cancer (CRPC) is seriously lack of T cell infiltration, which greatly limits the clinical application of immunotherapy, but the mechanism is unclear. In the present study, in silico analyses and experimental data show that HnRNP L was significantly negatively correlated with CD4+ and CD8+ <em>T</em> cells infiltration in patients; besides, we found deficiency of HnRNP L recruites CD4+ and CD8+ <em>T</em> cells infiltration and impairs tumorigenesis. Mechanically, HnRNP L enhanced the translation of c-Myc and then promoted CXCL8 secretion via alternative splicing of EIF4G1. In vivo, inhibition of EIF4G1 by the inhibitor, SBI-0640756, attenuated HnRNP <span>l</span>-induced tumor progression and immunosuppressive activity. And most of all, therapeutic synergy between HnRNP L knockdown and Anti-PD-1 could significantly suppress xenograft prostate cancer growth. In summary, this study revealled the molecular mechanism of HnRNP L regulating the immune infiltration, which provides a new theoretical basis for overcoming the limitation of immunotherapy for CRPC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101109"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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