Nicole C. Riedel, Carolin Walter, Flavia W. de Faria, Lea Altendorf, Paula Aust, Carolin Göbel, Archana Verma, Annika Ballast, Ivan Bedzhov, Rajanya Roy, Daniel Münter, Erik Schüftan, Thomas K. Albert, Claudia Rössig, Pascal Johann, Barbara von Zezschwitz, Sarah Sandmann, Julian Varghese, Christian Thomas, Ulrich Schüller, Jan M. Bruder, Kornelius Kerl
The cover image is based on the article In vivo intratumoral heterogeneity in a dish: scalable forebrain organoid models of embryonal brain tumors for high-throughput personalized drug discovery by Nicole C. Riedel et al., https://doi.org/10.1002/cac2.70074.
封面图片基于Nicole C. Riedel等人的文章《培养皿中的体内肿瘤内异质性：用于高通量个性化药物发现的胚胎性脑肿瘤的可扩展前脑类器官模型》，https://doi.org/10.1002/cac2.70074。
{"title":"Cover Image, Volume 45, Issue 12","authors":"Nicole C. Riedel, Carolin Walter, Flavia W. de Faria, Lea Altendorf, Paula Aust, Carolin Göbel, Archana Verma, Annika Ballast, Ivan Bedzhov, Rajanya Roy, Daniel Münter, Erik Schüftan, Thomas K. Albert, Claudia Rössig, Pascal Johann, Barbara von Zezschwitz, Sarah Sandmann, Julian Varghese, Christian Thomas, Ulrich Schüller, Jan M. Bruder, Kornelius Kerl","doi":"10.1002/cac2.70085","DOIUrl":"https://doi.org/10.1002/cac2.70085","url":null,"abstract":"<p>The cover image is based on the article <i>In vivo intratumoral heterogeneity in a dish: scalable forebrain organoid models of embryonal brain tumors for high-throughput personalized drug discovery</i> by Nicole C. Riedel et al., \u0000https://doi.org/10.1002/cac2.70074. \u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848406","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}
Carine Ngo, Léo Colmet-Daage, Julien Vibert, Clémence Hénon, Daniel Pissaloux, Alexander Valent, Jia Xiang Jin, Riwan Brillet, Julien Masliah-Planchon, Gaëlle Pierron, Ludovic Lacroix, Etienne Rouleau, Cyril Roussel-Simonin, Lilian Lecorgne, Clémence Astier, Marlène Garrido, Rastislav Bahleda, Benjamin Verret, Axel Le Cesne, Charles Honore, Matthieu Faron, Wolf Herman Fridman, Catherine Sautès-Fridman, Jean-Michel Coindre, Jean-Yves Scoazec, Joshua J Waterfall, Franck Bourdeaut, Thomas G. P. Grünewald, Jean-Yves Blay, Franck Tirode, Sophie Postel-Vinay
<p>Epithelioid sarcoma (EpS) is an aggressive soft tissue sarcoma characterized by switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) loss [<span>1</span>]. Conventionally, EpS is histologically classified as either distal or proximal subtype, each exhibiting distinct clinical behaviors; these sometimes co-exist as “hybrid” EpS [<span>2, 3</span>]. Differential diagnosis from other SMARCB1-deficient tumors, such as extracranial extrarenal rhabdoid tumors (EERTs), can be challenging [<span>4</span>]. Beyond phenotypic diversity, EpS molecular heterogeneity remains poorly understood. To address this, we aimed to build a molecular classification and explore inter- and intra-tumor heterogeneity, using multi-omics profiling.</p><p>We profiled 33 EpSs and 3 EERTs using whole-exome sequencing (WES), DNA methylation, and bulk RNA-sequencing (RNA-seq); single-cell RNA-sequencing (scRNA-seq) and 10x Genomics Visium spatial transcriptomics were performed on 8 and 4 EpSs, respectively (Figure 1A, Supplementary Materials and Methods). Cases were reviewed by two senior pathologists and classified by histology (14 distal, 14 proximal, 5 hybrid EpSs) (Supplementary Figure S1, Supplementary Tables S1-S2).</p><p>Unsupervised RNA-seq clustering identified two EpS transcriptomic subtypes (Figure 1B): (i) distal-like (<i>n</i> = 20) — including all distal EpS, 2 proximal and 4 hybrid EpSs — enriched in cell adhesion, circulatory system development genes and extracellular matrix; (ii) proximal-like (<i>n</i> = 13) — comprising 12 proximal and 1 hybrid EpSs — enriched in synapse organization, response to wounding and macrophage activation (Supplementary Figure S2A, Supplementary Table S3). Gene set enrichment analysis revealed a significant enrichment in epithelial-mesenchymal transition (EMT) and ultraviolet response in distal-like EpS compared to proximal-like EpS (normalized enrichment score = 1.80 and 1.66, respectively; false discovery rate < 25%; <i>p</i> < 0.05) (Supplementary Figure S2B, Supplementary Table S4).</p><p>We explored mechanisms of SMARCB1 loss in 31 EpSs and 3 EERTs, using WES, targeted next-generation sequencing, single-nucleotide polymorphism array, shallow whole-genome sequencing, DNA methylation and fluorescence in situ hybridization – depending on material availability (Supplementary Figure S3A, Supplementary Table S5). Biallelic <i>SMARCB1</i> inactivation was identified in 16 (51.6%) of 31 EpSs (mostly homozygous deletions), without germline <i>SMARCB1</i> alteration. Heterozygous loss-of-function alterations were found in 14/31 (45.2%) EpSs. <i>SMARCB1</i> alteration types were similar across EpS transcriptomic subtypes and unrelated to <i>SMARCB1</i> mRNA levels (Supplementary Figure S3B-D).</p><p>Recurrent alterations, excluding <i>SMARCB1</i>, occurred in up to13% of EpSs (Supplementary Figure S3A, Supplementary Tables S6-S7). Median tumor mutatio
{"title":"Multi-omics profiling identified two epithelioid sarcoma molecular subtypes with distinct signaling and immune characteristics","authors":"Carine Ngo, Léo Colmet-Daage, Julien Vibert, Clémence Hénon, Daniel Pissaloux, Alexander Valent, Jia Xiang Jin, Riwan Brillet, Julien Masliah-Planchon, Gaëlle Pierron, Ludovic Lacroix, Etienne Rouleau, Cyril Roussel-Simonin, Lilian Lecorgne, Clémence Astier, Marlène Garrido, Rastislav Bahleda, Benjamin Verret, Axel Le Cesne, Charles Honore, Matthieu Faron, Wolf Herman Fridman, Catherine Sautès-Fridman, Jean-Michel Coindre, Jean-Yves Scoazec, Joshua J Waterfall, Franck Bourdeaut, Thomas G. P. Grünewald, Jean-Yves Blay, Franck Tirode, Sophie Postel-Vinay","doi":"10.1002/cac2.70077","DOIUrl":"10.1002/cac2.70077","url":null,"abstract":"<p>Epithelioid sarcoma (EpS) is an aggressive soft tissue sarcoma characterized by switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) loss [<span>1</span>]. Conventionally, EpS is histologically classified as either distal or proximal subtype, each exhibiting distinct clinical behaviors; these sometimes co-exist as “hybrid” EpS [<span>2, 3</span>]. Differential diagnosis from other SMARCB1-deficient tumors, such as extracranial extrarenal rhabdoid tumors (EERTs), can be challenging [<span>4</span>]. Beyond phenotypic diversity, EpS molecular heterogeneity remains poorly understood. To address this, we aimed to build a molecular classification and explore inter- and intra-tumor heterogeneity, using multi-omics profiling.</p><p>We profiled 33 EpSs and 3 EERTs using whole-exome sequencing (WES), DNA methylation, and bulk RNA-sequencing (RNA-seq); single-cell RNA-sequencing (scRNA-seq) and 10x Genomics Visium spatial transcriptomics were performed on 8 and 4 EpSs, respectively (Figure 1A, Supplementary Materials and Methods). Cases were reviewed by two senior pathologists and classified by histology (14 distal, 14 proximal, 5 hybrid EpSs) (Supplementary Figure S1, Supplementary Tables S1-S2).</p><p>Unsupervised RNA-seq clustering identified two EpS transcriptomic subtypes (Figure 1B): (i) distal-like (<i>n</i> = 20) — including all distal EpS, 2 proximal and 4 hybrid EpSs — enriched in cell adhesion, circulatory system development genes and extracellular matrix; (ii) proximal-like (<i>n</i> = 13) — comprising 12 proximal and 1 hybrid EpSs — enriched in synapse organization, response to wounding and macrophage activation (Supplementary Figure S2A, Supplementary Table S3). Gene set enrichment analysis revealed a significant enrichment in epithelial-mesenchymal transition (EMT) and ultraviolet response in distal-like EpS compared to proximal-like EpS (normalized enrichment score = 1.80 and 1.66, respectively; false discovery rate < 25%; <i>p</i> < 0.05) (Supplementary Figure S2B, Supplementary Table S4).</p><p>We explored mechanisms of SMARCB1 loss in 31 EpSs and 3 EERTs, using WES, targeted next-generation sequencing, single-nucleotide polymorphism array, shallow whole-genome sequencing, DNA methylation and fluorescence in situ hybridization – depending on material availability (Supplementary Figure S3A, Supplementary Table S5). Biallelic <i>SMARCB1</i> inactivation was identified in 16 (51.6%) of 31 EpSs (mostly homozygous deletions), without germline <i>SMARCB1</i> alteration. Heterozygous loss-of-function alterations were found in 14/31 (45.2%) EpSs. <i>SMARCB1</i> alteration types were similar across EpS transcriptomic subtypes and unrelated to <i>SMARCB1</i> mRNA levels (Supplementary Figure S3B-D).</p><p>Recurrent alterations, excluding <i>SMARCB1</i>, occurred in up to13% of EpSs (Supplementary Figure S3A, Supplementary Tables S6-S7). Median tumor mutatio","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1760-1766"},"PeriodicalIF":24.9,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630218","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}
Chuanhua Zhao, Jun Zhao, Yigui Chen, Bo Liu, Yangfeng Du, Chenglin Li, Jingdong Zhang, Mudan Yang, Ying Liu, Yuxian Bai, Suyi Li, Ruixing Zhang, Fangling Ning, Yanping Liu, Kai Zou, Qi Zhang, Yijiao Xie, Yuping An, Jianming Xu
<p>In 2022, gastric cancer (GC) ranked as the fifth most common cancer and the third leading cause of cancer death in China, with 358,672 new cases and 260,372 deaths, accounting for 37.0% and 39.4% of global cases, respectively [<span>1</span>]. Previous studies have shown that 25.9% and 36.5% of GC patients in China were diagnosed at stages III and IV, respectively, with 5-year overall survival (OS) rates of 33.0% for stage III and 5.5% for stage IV [<span>2, 3</span>].</p><p>A previous study reported that human epidermal growth factor receptor 2 (HER2) positivity was found in 8.8% of Chinese patients with gastric adenocarcinoma [<span>4</span>]. Building on the ToGA trial [<span>5</span>], which established trastuzumab plus chemotherapy as the standard first-line treatment for HER2-positive GC, the KEYNOTE-811 trial [<span>6</span>] demonstrated superior progression-free survival (PFS) combined with immune checkpoint inhibitors, establishing this regimen as the current standard of care. Recent interim-analysis of the DESTINY-Gastric04 trial revealed that trastuzumab deruxtecan significantly improved overall survival compared to chemotherapy-based regimen in patients with HER2-positive gastric/gastroesophageal junction (GC/GEJ) carcinoma, leading to its establishment as second-line therapy [<span>7</span>]. Furthermore, zanidatamab, a HER2-targeted bispecific antibody against extracellular domains (ECDs) 2 and 4, has shown promising efficacy as both a monotherapy and in combination with chemotherapy for HER2-overexpressing GC in the second-line setting [<span>8</span>].</p><p>Anbenitamab, also known as SYS6092 (KN026), is a bispecific antibody that simultaneously binds to two distinct HER2 epitopes, the same extracellular domains targeted by trastuzumab (domain IV) and pertuzumab (domain II) [<span>9</span>]. Here, we present the results of a phase II study (NCT05427383) evaluating the safety and efficacy of anbenitamab plus chemotherapy in patients with HER2-positive advanced GC who failed previous therapy containing trastuzumab. Patients with locally advanced or metastatic HER2-positive GC/GEJ carcinoma who failed previous therapy containing trastuzumab were assigned to receive anbenitamab (30 mg/kg, Day 1, every 3 weeks [Q3W]) plus paclitaxel (175 mg/m<sup>2</sup>, Day 1, Q3W) or irinotecan (125 mg/m<sup>2</sup>, Day 1 and Day 8, Q3W) at investigators' discretion based on previous treatment. Full methodology is detailed in the Supplementary Materials.</p><p>Between April 7, 2022, and January 12, 2023, 39 patients were enrolled across 19 hospitals in China (Supplementary Table S1) and were assigned to receive either anbenitamab plus paclitaxel (<i>n</i> = 20) or anbenitamab plus irinotecan (<i>n</i> = 19; Supplementary Figure S1). Baseline patient characteristics are detailed in Supplementary Table S2. Eastern Cooperative Oncology Group performance status (ECOG PS) scores of 0 and 1 were reported in 7 (17.9%) and 32 (82.1%) patients, respect
{"title":"Anbenitamab in combination with chemotherapy in patients with HER2-positive gastric or gastroesophageal junction carcinoma who failed previous therapy containing trastuzumab: a multicenter, phase II study (KC-WISE 01)","authors":"Chuanhua Zhao, Jun Zhao, Yigui Chen, Bo Liu, Yangfeng Du, Chenglin Li, Jingdong Zhang, Mudan Yang, Ying Liu, Yuxian Bai, Suyi Li, Ruixing Zhang, Fangling Ning, Yanping Liu, Kai Zou, Qi Zhang, Yijiao Xie, Yuping An, Jianming Xu","doi":"10.1002/cac2.70080","DOIUrl":"10.1002/cac2.70080","url":null,"abstract":"<p>In 2022, gastric cancer (GC) ranked as the fifth most common cancer and the third leading cause of cancer death in China, with 358,672 new cases and 260,372 deaths, accounting for 37.0% and 39.4% of global cases, respectively [<span>1</span>]. Previous studies have shown that 25.9% and 36.5% of GC patients in China were diagnosed at stages III and IV, respectively, with 5-year overall survival (OS) rates of 33.0% for stage III and 5.5% for stage IV [<span>2, 3</span>].</p><p>A previous study reported that human epidermal growth factor receptor 2 (HER2) positivity was found in 8.8% of Chinese patients with gastric adenocarcinoma [<span>4</span>]. Building on the ToGA trial [<span>5</span>], which established trastuzumab plus chemotherapy as the standard first-line treatment for HER2-positive GC, the KEYNOTE-811 trial [<span>6</span>] demonstrated superior progression-free survival (PFS) combined with immune checkpoint inhibitors, establishing this regimen as the current standard of care. Recent interim-analysis of the DESTINY-Gastric04 trial revealed that trastuzumab deruxtecan significantly improved overall survival compared to chemotherapy-based regimen in patients with HER2-positive gastric/gastroesophageal junction (GC/GEJ) carcinoma, leading to its establishment as second-line therapy [<span>7</span>]. Furthermore, zanidatamab, a HER2-targeted bispecific antibody against extracellular domains (ECDs) 2 and 4, has shown promising efficacy as both a monotherapy and in combination with chemotherapy for HER2-overexpressing GC in the second-line setting [<span>8</span>].</p><p>Anbenitamab, also known as SYS6092 (KN026), is a bispecific antibody that simultaneously binds to two distinct HER2 epitopes, the same extracellular domains targeted by trastuzumab (domain IV) and pertuzumab (domain II) [<span>9</span>]. Here, we present the results of a phase II study (NCT05427383) evaluating the safety and efficacy of anbenitamab plus chemotherapy in patients with HER2-positive advanced GC who failed previous therapy containing trastuzumab. Patients with locally advanced or metastatic HER2-positive GC/GEJ carcinoma who failed previous therapy containing trastuzumab were assigned to receive anbenitamab (30 mg/kg, Day 1, every 3 weeks [Q3W]) plus paclitaxel (175 mg/m<sup>2</sup>, Day 1, Q3W) or irinotecan (125 mg/m<sup>2</sup>, Day 1 and Day 8, Q3W) at investigators' discretion based on previous treatment. Full methodology is detailed in the Supplementary Materials.</p><p>Between April 7, 2022, and January 12, 2023, 39 patients were enrolled across 19 hospitals in China (Supplementary Table S1) and were assigned to receive either anbenitamab plus paclitaxel (<i>n</i> = 20) or anbenitamab plus irinotecan (<i>n</i> = 19; Supplementary Figure S1). Baseline patient characteristics are detailed in Supplementary Table S2. Eastern Cooperative Oncology Group performance status (ECOG PS) scores of 0 and 1 were reported in 7 (17.9%) and 32 (82.1%) patients, respect","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1755-1759"},"PeriodicalIF":24.9,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581732","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}
Jingbo Fu, Yanping Wei, Yun Yang, Xinwei Yang, Tao Ouyang, Xianming Wang, Shuzhen Chen, Zenglin Liu, Yu Su, Jing Fu, Miao Yu, Haihua Qian, Hao Song, Shuo Xu, Ru Zhao, Xue Jiang, Yunfei Huo, Man Zhang, Pinhua Yang, Zhao Yang, Kui Wang, Liang Li, Hongyang Wang
The cover image is based on the article Intranuclear paraspeckle-circular RNA TACC3 assembly forms RNA-DNA hybrids to facilitate MASH-related hepatocellular carcinoma growth in an m6A-dependent manner by Hongyang Wang et al., https://doi.org/10.1002/cac2.70061.
The cover image is based on the article CD24 is a promising immunotherapeutic target for enhancing efficacy of third-generation EGFR-TKIs on EGFR-mutated lung cancer by Jiaqi Liang et al., https://doi.org/10.1002/cac2.70068.
Rui Zhou, Shiyang Zheng, Daquan Wang, Fang Dong, Hongmei Zhang, Tao Zhang, Qiaoting Luo, Biaoshui Liu, Hui Liu, Jun Zhang, Fangjie Liu, Bin Wang, Likun Chen, Yonggao Mou, Kangqiang Peng, Bo Qiu, Hui Liu
<div> <section> <h3> Background</h3> <p>The prognosis for non-small cell lung cancer (NSCLC) patients with extensive brain metastases (BMs) treated with radiotherapy alone remains poor. Based on the synergistic potential of radiotherapy and angiogenesis inhibitors, we initiated this phase II study to assess the efficacy and safety of combining bevacizumab (Bev) with fractionated stereotactic radiotherapy (FSRT) in managing extensive BMs in NSCLC patients who had stable extracranial disease.</p> </section> <section> <h3> Methods</h3> <p>Patients with extensive BMs from NSCLC, deemed unsuitable for stereotactic radiosurgery, were prospectively enrolled following multidisciplinary tumor board evaluation. Patients received FSRT (40 Gy in 10 fractions or 30 Gy in 5 fractions) in combination with Bev (7.5 mg/kg on day 1 prior to FSRT and on day 21 post-FSRT). The primary endpoint was intracranial progression-free survival (IPFS). Secondary endpoints included overall survival, progression-free survival, quality of life (QOL), and toxicities. For comparison, NSCLC patients with extensive BMs treated with whole-brain radiotherapy (WBRT) plus FSRT or FSRT alone were matched 1:1 with the study group (Bev + FSRT) using the propensity score matching.</p> </section> <section> <h3> Results</h3> <p>One hundred and six patients were included in the Bev + FSRT group, with a median follow-up duration of 35.8 months. The median IPFS was 18.3 months (95% confidence interval, 15.2-23.3 months). The Bev + FSRT group showed a significant improvement in IPFS compared to both the WBRT + FSRT group (9.6 months, P < 0.001) and the FSRT alone group (8.9 months, P < 0.001). Treatment was well tolerated, with grade 1 radiation necrosis in 1 patient. Bev + FSRT treatment significantly reduced tumor volume (<i>P</i> < 0.001), peritumoral edema volume (<i>P</i> = 0.004), and vascular leakage (<i>P</i> < 0.001). Furthermore, QOL was significantly improved after Bev + FSRT treatment, particularly in patients with symptomatic extensive BMs.</p> </section> <section> <h3> Conclusion</h3> <p>These findings support the combination of Bev and FSRT as a safe and effective treatment strategy for extensive BMs in NSCLC patients, offering improved intracranial disease control and symptom relief while avoiding the neurotoxicity associated with WBRT. A randomized trial is warranted to validate the findings of the current study.</p> </section> <section> <h3> Trial registration</h3> <p
{"title":"Efficacy and safety of combining bevacizumab and fractionated stereotactic radiotherapy for extensive brain metastases in patients with non-small cell lung cancer: a prospective phase II study (GASTO-1053)","authors":"Rui Zhou, Shiyang Zheng, Daquan Wang, Fang Dong, Hongmei Zhang, Tao Zhang, Qiaoting Luo, Biaoshui Liu, Hui Liu, Jun Zhang, Fangjie Liu, Bin Wang, Likun Chen, Yonggao Mou, Kangqiang Peng, Bo Qiu, Hui Liu","doi":"10.1002/cac2.70078","DOIUrl":"10.1002/cac2.70078","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The prognosis for non-small cell lung cancer (NSCLC) patients with extensive brain metastases (BMs) treated with radiotherapy alone remains poor. Based on the synergistic potential of radiotherapy and angiogenesis inhibitors, we initiated this phase II study to assess the efficacy and safety of combining bevacizumab (Bev) with fractionated stereotactic radiotherapy (FSRT) in managing extensive BMs in NSCLC patients who had stable extracranial disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with extensive BMs from NSCLC, deemed unsuitable for stereotactic radiosurgery, were prospectively enrolled following multidisciplinary tumor board evaluation. Patients received FSRT (40 Gy in 10 fractions or 30 Gy in 5 fractions) in combination with Bev (7.5 mg/kg on day 1 prior to FSRT and on day 21 post-FSRT). The primary endpoint was intracranial progression-free survival (IPFS). Secondary endpoints included overall survival, progression-free survival, quality of life (QOL), and toxicities. For comparison, NSCLC patients with extensive BMs treated with whole-brain radiotherapy (WBRT) plus FSRT or FSRT alone were matched 1:1 with the study group (Bev + FSRT) using the propensity score matching.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>One hundred and six patients were included in the Bev + FSRT group, with a median follow-up duration of 35.8 months. The median IPFS was 18.3 months (95% confidence interval, 15.2-23.3 months). The Bev + FSRT group showed a significant improvement in IPFS compared to both the WBRT + FSRT group (9.6 months, P < 0.001) and the FSRT alone group (8.9 months, P < 0.001). Treatment was well tolerated, with grade 1 radiation necrosis in 1 patient. Bev + FSRT treatment significantly reduced tumor volume (<i>P</i> < 0.001), peritumoral edema volume (<i>P</i> = 0.004), and vascular leakage (<i>P</i> < 0.001). Furthermore, QOL was significantly improved after Bev + FSRT treatment, particularly in patients with symptomatic extensive BMs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings support the combination of Bev and FSRT as a safe and effective treatment strategy for extensive BMs in NSCLC patients, offering improved intracranial disease control and symptom relief while avoiding the neurotoxicity associated with WBRT. A randomized trial is warranted to validate the findings of the current study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial registration</h3>\u0000 \u0000 <p","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1739-1754"},"PeriodicalIF":24.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511785","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}
Junchi Huang, Peter Larsson, Maryam Kakay Afshari, Paloma Tejera Nevado, Tajana Tešan Tomić, André Fehr, Fredrik Jäwert, Göran Stenman, Mattias K. Andersson
<p>Adenoid cystic carcinoma (ACC) is an aggressive glandular cancer primarily affecting the major and minor salivary glands but may also occur in other anatomical locations such as the breast, prostate, lungs, and skin [<span>1, 2</span>]. ACC has a poor long-term prognosis due to frequent recurrences and distant metastases and is unresponsive to all so far tested systemic therapies. The <i>MYB</i> proto-oncogene, transcription factor (<i>MYB</i>), is a key oncogenic driver activated by gene fusions in ACC [<span>3-7</span>]. We have previously demonstrated that the canonical <i>MYB</i>::nuclear factor I B (<i>NFIB</i>) fusion (<i>MYB::NFIB</i>) is targetable by insulin-like growth factor 1 receptor/AKT serine-threonine kinase (IGF1R/AKT) inhibitors, demonstrating that it is indeed an actionable target in ACC [<span>5</span>].</p><p>To identify more effective therapeutic options for ACC patients, we conducted an in vitro drug screen using carefully validated <i>MYB::NFIB</i>-positive ACC cells and a custom-made library of more than 300 small-molecule inhibitors covering important druggable targets in precision oncology (Supplementary Materials). Notably, cyclin-dependent kinase (CDK) inhibitors emerged among the most effective agents that reduced the viability of ACC cells (Figure 1A, Supplementary Tables S1-S2). We further tested 8 different U.S. Food and Drug Administration (FDA)-approved/phase II–III CDK inhibitors, of which dinaciclib (a pan-CDK inhibitor) showed by far the highest potency (half maximal inhibitory concentration [IC50]: 10–13 nmol/L, <i>P</i> < 0.001) (Figure 1B, Supplementary Figure S1A). ACC cells were significantly less sensitive to U.S. FDA-approved CDK4/6 inhibitors, such as palbociclib and ribociclib, than to dinaciclib. The ACC cell line, UM-HACC-2A, showed similar sensitivity to dinaciclib as ACCX11 and ACC67 cells, whereas control pleomorphic adenoma (PA) cells were significantly less responsive (Supplementary Figure S1B). Additional top hits from our screen included histone deacetylase, proteasome, and IGF1R-phosphoinositide 3-kinase (PI3K)-AKT inhibitors, consistent with our previous findings [<span>5, 8</span>] and thus validating our screening approach.</p><p>Dinaciclib caused a significant decrease in ACC spheroid formation at nanomolar concentrations (Figure 1C, Supplementary Figure S2A), suggesting that it inhibits cell division of immature stem-like ACC cells capable of tumor initiation. Flow cytometry analysis of dinaciclib-treated ACC cells revealed reduced S-phase entry and accumulation of cells in the G1 and G2/M phases, indicating cell cycle arrest at multiple checkpoints (Supplementary Figures S2B-C and S3). To test if CDK inhibition leads to apoptosis in ACC cells, we treated ACCX11 and ACC67 cells with CDK inhibitors at different concentrations for 24 h. Dinaciclib induced apoptosis at low concentrations, whereas Flavopiridol and AT7519 caused apoptosis at much higher concentrations; the other teste
{"title":"Pan-cyclin-dependent kinase inhibition is a potential treatment for adenoid cystic carcinoma that downregulates the MYB::NFIB fusion and induces tumor regression","authors":"Junchi Huang, Peter Larsson, Maryam Kakay Afshari, Paloma Tejera Nevado, Tajana Tešan Tomić, André Fehr, Fredrik Jäwert, Göran Stenman, Mattias K. Andersson","doi":"10.1002/cac2.70079","DOIUrl":"10.1002/cac2.70079","url":null,"abstract":"<p>Adenoid cystic carcinoma (ACC) is an aggressive glandular cancer primarily affecting the major and minor salivary glands but may also occur in other anatomical locations such as the breast, prostate, lungs, and skin [<span>1, 2</span>]. ACC has a poor long-term prognosis due to frequent recurrences and distant metastases and is unresponsive to all so far tested systemic therapies. The <i>MYB</i> proto-oncogene, transcription factor (<i>MYB</i>), is a key oncogenic driver activated by gene fusions in ACC [<span>3-7</span>]. We have previously demonstrated that the canonical <i>MYB</i>::nuclear factor I B (<i>NFIB</i>) fusion (<i>MYB::NFIB</i>) is targetable by insulin-like growth factor 1 receptor/AKT serine-threonine kinase (IGF1R/AKT) inhibitors, demonstrating that it is indeed an actionable target in ACC [<span>5</span>].</p><p>To identify more effective therapeutic options for ACC patients, we conducted an in vitro drug screen using carefully validated <i>MYB::NFIB</i>-positive ACC cells and a custom-made library of more than 300 small-molecule inhibitors covering important druggable targets in precision oncology (Supplementary Materials). Notably, cyclin-dependent kinase (CDK) inhibitors emerged among the most effective agents that reduced the viability of ACC cells (Figure 1A, Supplementary Tables S1-S2). We further tested 8 different U.S. Food and Drug Administration (FDA)-approved/phase II–III CDK inhibitors, of which dinaciclib (a pan-CDK inhibitor) showed by far the highest potency (half maximal inhibitory concentration [IC50]: 10–13 nmol/L, <i>P</i> < 0.001) (Figure 1B, Supplementary Figure S1A). ACC cells were significantly less sensitive to U.S. FDA-approved CDK4/6 inhibitors, such as palbociclib and ribociclib, than to dinaciclib. The ACC cell line, UM-HACC-2A, showed similar sensitivity to dinaciclib as ACCX11 and ACC67 cells, whereas control pleomorphic adenoma (PA) cells were significantly less responsive (Supplementary Figure S1B). Additional top hits from our screen included histone deacetylase, proteasome, and IGF1R-phosphoinositide 3-kinase (PI3K)-AKT inhibitors, consistent with our previous findings [<span>5, 8</span>] and thus validating our screening approach.</p><p>Dinaciclib caused a significant decrease in ACC spheroid formation at nanomolar concentrations (Figure 1C, Supplementary Figure S2A), suggesting that it inhibits cell division of immature stem-like ACC cells capable of tumor initiation. Flow cytometry analysis of dinaciclib-treated ACC cells revealed reduced S-phase entry and accumulation of cells in the G1 and G2/M phases, indicating cell cycle arrest at multiple checkpoints (Supplementary Figures S2B-C and S3). To test if CDK inhibition leads to apoptosis in ACC cells, we treated ACCX11 and ACC67 cells with CDK inhibitors at different concentrations for 24 h. Dinaciclib induced apoptosis at low concentrations, whereas Flavopiridol and AT7519 caused apoptosis at much higher concentrations; the other teste","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1734-1738"},"PeriodicalIF":24.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494756","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}
Rui Tang, Yan Sun, Ao Deng, Jiahe Liu, Peijin Dai, Jing Chen, Chaoqun Deng, Hui Liu, Yuhang Hai, Yanran Tong, Yan-e Du, Manran Liu, Haojun Luo
<div> <section> <h3> Background</h3> <p>Metastasis is the leading cause of cancer-related mortality, with circulating tumor cell (CTC) clusters serving as highly efficient precursors of distant metastasis. Survival of CTC clusters in the bloodstream is the primary contributor to tumor metastasis. However, the underlying mechanisms of how CTC clusters respond to the blood environment and drive metastasis remain elusive. This study aimed to elucidate the potential mechanisms that enable CTC clusters to adapt and survive in the bloodstream.</p> </section> <section> <h3> Methods</h3> <p>CTC clusters were detected using a microfluidic system in cancer patients, as well as in patient-derived xenograft (PDX), cell line-derived xenograft, and syngeneic models. The key molecules responsible for the adaptive survival of CTC clusters were characterized using RNA-sequencing (RNA-seq), gene interference, and flow cytometry. To investigate the underlying mechanisms of adaptive survival, RNA-seq, targeted metabolomics, isotope tracing experiments, chromatin immunoprecipitation (ChIP) sequencing, and immunofluorescence (IF) staining were employed. The therapeutic potential of survival pathway inhibitor combined with chemotherapy drug was evaluated in patient-derived CTCs and the PDX model.</p> </section> <section> <h3> Results</h3> <p>CTC clusters exhibited superior survival and metastatic capacity compared to single CTCs and were associated with adverse clinical outcomes. The unfolded protein response mediator protein kinase R-like endoplasmic reticulum kinase (PERK) was activated in CTC clusters and maintained S-adenosylmethionine (SAM) availability, facilitating their adaptive survival in the bloodstream. Mechanistically, PERK mediated the upregulation of activating transcription factor 4 (ATF4), which enhanced methionine adenosyltransferase 2A (MAT2A) expression, contributing to SAM synthesis. Increased SAM enhanced H3K4me3 modification of the platelet-derived growth factor B (<i>PDGFB</i>) promoter, leading to elevated PDGFB secretion and its accumulation in the intercellular region within CTC clusters. PDGFB functioned as a shared survival signal, triggering the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway via platelet-derived growth factor receptor beta (PDGFRβ), supporting CTC cluster survival in the bloodstream. Inhibition of PERK and PDGFRβ profoundly impaired the survival signaling and suppressed the metastatic dissemination of CTC clusters.</p> </section> <section> <h3> Conclusions</h3> <p>Our findings revealed a PERK/MAT2A/PDGFB axi
{"title":"Unfolded protein response kinase PERK supports survival and metastasis of circulating tumor cell clusters via SAM synthesis and H3K4me3-dependent PDGFB signaling","authors":"Rui Tang, Yan Sun, Ao Deng, Jiahe Liu, Peijin Dai, Jing Chen, Chaoqun Deng, Hui Liu, Yuhang Hai, Yanran Tong, Yan-e Du, Manran Liu, Haojun Luo","doi":"10.1002/cac2.70072","DOIUrl":"10.1002/cac2.70072","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metastasis is the leading cause of cancer-related mortality, with circulating tumor cell (CTC) clusters serving as highly efficient precursors of distant metastasis. Survival of CTC clusters in the bloodstream is the primary contributor to tumor metastasis. However, the underlying mechanisms of how CTC clusters respond to the blood environment and drive metastasis remain elusive. This study aimed to elucidate the potential mechanisms that enable CTC clusters to adapt and survive in the bloodstream.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CTC clusters were detected using a microfluidic system in cancer patients, as well as in patient-derived xenograft (PDX), cell line-derived xenograft, and syngeneic models. The key molecules responsible for the adaptive survival of CTC clusters were characterized using RNA-sequencing (RNA-seq), gene interference, and flow cytometry. To investigate the underlying mechanisms of adaptive survival, RNA-seq, targeted metabolomics, isotope tracing experiments, chromatin immunoprecipitation (ChIP) sequencing, and immunofluorescence (IF) staining were employed. The therapeutic potential of survival pathway inhibitor combined with chemotherapy drug was evaluated in patient-derived CTCs and the PDX model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CTC clusters exhibited superior survival and metastatic capacity compared to single CTCs and were associated with adverse clinical outcomes. The unfolded protein response mediator protein kinase R-like endoplasmic reticulum kinase (PERK) was activated in CTC clusters and maintained S-adenosylmethionine (SAM) availability, facilitating their adaptive survival in the bloodstream. Mechanistically, PERK mediated the upregulation of activating transcription factor 4 (ATF4), which enhanced methionine adenosyltransferase 2A (MAT2A) expression, contributing to SAM synthesis. Increased SAM enhanced H3K4me3 modification of the platelet-derived growth factor B (<i>PDGFB</i>) promoter, leading to elevated PDGFB secretion and its accumulation in the intercellular region within CTC clusters. PDGFB functioned as a shared survival signal, triggering the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway via platelet-derived growth factor receptor beta (PDGFRβ), supporting CTC cluster survival in the bloodstream. Inhibition of PERK and PDGFRβ profoundly impaired the survival signaling and suppressed the metastatic dissemination of CTC clusters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings revealed a PERK/MAT2A/PDGFB axi","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1706-1733"},"PeriodicalIF":24.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487926","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}
Huanhuan Cui, Yuechao Yang, Sen Li, Yan Hao, Mingtao Feng, Changshuai Zhou, Xin Chen, Yang Gao, Lei Chen, Xiaojun Wu, Weiguo Hu, Liangdong Li, Yiqun Cao
Background
Brain metastasis, a leading cause of death in patients with lung adenocarcinoma (LUAD), arises from tumor cells adapting to the unique microenvironment of the brain through metabolic remodeling regulated by key oncogenes. Here, we aimed to determine the role of high mobility group protein box 3 (HMGB3) in regulating tumor cell metabolism to promote the progression and brain metastasis of LUAD.
Methods
A LUAD cell model predisposed to brain metastasis was established, followed by differential gene expression analysis. HMGB3 expression was quantified via single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, with clinical relevance assessed in two retrospective cohorts: the primary LUAD and the LUAD brain metastasis cohorts. Gene enrichment analysis of scRNA-seq and bulk RNA-seq data, along with Western blotting, were performed to identify HMGB3-associated pathways. Co-immunoprecipitation combined with mass spectrometry was used to detect HMGB3-interacting proteins. Gain-of-function, loss-of-function and rescue experiments targeting HMGB3 downstream pathways were conducted in vitro and in vivo.
Results
HMGB3 expression was significantly elevated in both primary LUAD lesions and brain metastatic foci, and its upregulation was strongly associated with poor prognosis in LUAD patients, as well as in those with concomitant brain metastasis. HMGB3 enhanced the migration, invasion, and epithelial-mesenchymal transition (EMT) capabilities of LUAD cells in vitro and promoted the development of brain metastasis in vivo. Mechanistically, HMGB3 recruited and interacted with single-stranded DNA-binding protein 1 (SSBP1), inducing its nuclear translocation and reprogramming mitochondrial metabolism. This process elevated cytoplasmic reactive oxygen species levels, which subsequently activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathway through downregulating phosphatase and tensin homolog (PTEN), ultimately promoting tumor cell proliferation, migration, invasion, and EMT.
Conclusions
This study demonstrated HMGB3 as a key regulator of the brain metastasis of LUAD, orchestrating tumor cells’ metabolic adaptation to the brain microenvironment through modulation of mitochondrial metabolism, thereby offering potential therapeutic targets for LUAD brain metastases.
{"title":"HMGB3 promotes brain metastasis of lung adenocarcinoma by recruiting SSBP1 for nuclear translocation to remodel mitochondrial metabolism","authors":"Huanhuan Cui, Yuechao Yang, Sen Li, Yan Hao, Mingtao Feng, Changshuai Zhou, Xin Chen, Yang Gao, Lei Chen, Xiaojun Wu, Weiguo Hu, Liangdong Li, Yiqun Cao","doi":"10.1002/cac2.70075","DOIUrl":"10.1002/cac2.70075","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Brain metastasis, a leading cause of death in patients with lung adenocarcinoma (LUAD), arises from tumor cells adapting to the unique microenvironment of the brain through metabolic remodeling regulated by key oncogenes. Here, we aimed to determine the role of high mobility group protein box 3 (HMGB3) in regulating tumor cell metabolism to promote the progression and brain metastasis of LUAD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A LUAD cell model predisposed to brain metastasis was established, followed by differential gene expression analysis. HMGB3 expression was quantified via single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, with clinical relevance assessed in two retrospective cohorts: the primary LUAD and the LUAD brain metastasis cohorts. Gene enrichment analysis of scRNA-seq and bulk RNA-seq data, along with Western blotting, were performed to identify HMGB3-associated pathways. Co-immunoprecipitation combined with mass spectrometry was used to detect HMGB3-interacting proteins. Gain-of-function, loss-of-function and rescue experiments targeting HMGB3 downstream pathways were conducted in vitro and in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HMGB3 expression was significantly elevated in both primary LUAD lesions and brain metastatic foci, and its upregulation was strongly associated with poor prognosis in LUAD patients, as well as in those with concomitant brain metastasis. HMGB3 enhanced the migration, invasion, and epithelial-mesenchymal transition (EMT) capabilities of LUAD cells in vitro and promoted the development of brain metastasis in vivo. Mechanistically, HMGB3 recruited and interacted with single-stranded DNA-binding protein 1 (SSBP1), inducing its nuclear translocation and reprogramming mitochondrial metabolism. This process elevated cytoplasmic reactive oxygen species levels, which subsequently activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathway through downregulating phosphatase and tensin homolog (PTEN), ultimately promoting tumor cell proliferation, migration, invasion, and EMT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study demonstrated HMGB3 as a key regulator of the brain metastasis of LUAD, orchestrating tumor cells’ metabolic adaptation to the brain microenvironment through modulation of mitochondrial metabolism, thereby offering potential therapeutic targets for LUAD brain metastases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1676-1705"},"PeriodicalIF":24.9,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145451116","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}
Nicole C. Riedel, Carolin Walter, Flavia W. de Faria, Lea Altendorf, Paula Aust, Carolin Göbel, Archana Verma, Annika Ballast, Ivan Bedzhov, Rajanya Roy, Daniel Münter, Erik Schüftan, Thomas K. Albert, Claudia Rössig, Pascal Johann, Barbara von Zezschwitz, Sarah Sandmann, Julian Varghese, Christian Thomas, Ulrich Schüller, Jan M. Bruder, Kornelius Kerl
<p>Brain tumors are the most prevalent solid tumors in pediatrics, with atypical teratoid and rhabdoid tumor (ATRT) and embryonal tumor with multilayered rosettes (ETMR) presenting particularly poor prognoses.</p><p>The development of effective therapies is hampered by the lack of in vitro models that accurately reflect the complex tumor microenvironment (TME) and intratumoral heterogeneity observed in vivo. Traditional monolayer and tumorsphere/tumoroid cultures fail to capture these critical aspects [<span>1</span>], biasing them towards proliferative cell populations that respond differently to drugs than the original tumor. Likewise, in vivo models have fundamental limitations: they lack the primate-specific chromosome 19 microRNA cluster (C19MC) driver central to ETMR [<span>2</span>], cannot capture human-specific neurotoxicity, and are impractical for scalable drug screens [<span>1, 3</span>].</p><p>To address this, we developed a scalable and reproducible tumor-forebrain-organoid (TBO) model for ETMR and ATRT sonic hedgehog (ATRT-SHH) using a novel coaggregation method, which we characterized histologically and transcriptionally, and applied to drug screening, thereby identifying new candidate therapeutics for ETMR (Supplementary File of Methods). The automated workflow ensures high reproducibility and scalability, enabling the parallel generation of thousands of TBOs for high-throughput drug screening on tumor and TME.</p><p>To integrate central nervous system embryonal tumors into forebrain organoids (FBOs), which recapitulate key developmental trends and contain comparable cell populations found in first- and second-trimester fetal brains, we modified an automated FBO model [<span>4</span>] (Supplementary Figures S1, S3). For this, we employed a coaggregation approach, which involved mixing tumor and human-induced pluripotent stem cells (hiPSCs), and subsequently allowing their aggregation and joint maturation to form TBOs (Figure 1A). Confocal microscopy of whole-mount immunostained and cleared organoids revealed a broad and uniform integration of green fluorescent protein (GFP)-tagged human ETMR and ATRT-SHH (hETMR and hATRT-SHH) cells throughout FBOs (Figure 1B). The automated workflow allowed for the parallel generation of highly uniform and reproducible TBOs in 96-well plates, with low-standard error of the mean for the GFP signal intensity, indicative for tumor content, across multiple TBOs for both hETMR-FBO and hATRT-SHH-FBO (Figure 1C).</p><p>To comprehensively characterize TBOs, we employed immunohistochemistry (IHC) to examine the phenotype of hETMR- and hATRT-SHH-FBOs, with age-matched FBOs as controls. hETMR tumor areas were identified based on lin-28 homolog A (LIN28A) positivity, multilayered rosettes, and C19MC alterations, along with GFP immunofluorescence (Figure 1D, Supplementary Figure S4A-D). Control 1-month aged FBOs exhibited a predominantly immature phenotype [LIN28A<sup>+</sup>, SRY-box transcription factor 2 (
脑肿瘤是儿科最常见的实体肿瘤，非典型畸胎瘤和横纹肌样瘤（ATRT）和具有多层玫瑰花结的胚胎性肿瘤（ETMR）预后特别差。由于缺乏准确反映体内观察到的复杂肿瘤微环境（TME）和肿瘤内异质性的体外模型，阻碍了有效治疗方法的发展。传统的单层和肿瘤球/类肿瘤培养不能捕获这些关键方面，使它们偏向于对药物反应不同于原始肿瘤的增殖细胞群。同样，体内模型也有基本的局限性：它们缺乏灵长类动物特异性的19号染色体microRNA簇（C19MC）驱动程序，对ETMR[2]至关重要，不能捕获人类特异性的神经毒性，并且无法用于可扩展的药物筛选[1,3]。为了解决这个问题，我们使用一种新的共聚集方法开发了一种可扩展和可重复的肿瘤-前脑-类器官（TBO）模型，用于ETMR和ATRT音猬（ATRT- shh），我们对其进行了组织学和转录表征，并应用于药物筛选，从而确定了ETMR的新候选治疗方法（方法补充文件）。自动化工作流程确保了高再现性和可扩展性，能够并行生成数千个tbo，用于肿瘤和TME的高通量药物筛选。为了将中枢神经系统胚胎肿瘤整合到前脑类器官（FBOs）中，这概括了关键的发育趋势，并包含在妊娠早期和妊娠中期胎儿大脑中发现的可比较的细胞群，我们修改了一个自动化的FBO模型[4]（补充图S1， S3）。为此，我们采用了一种共聚集方法，将肿瘤细胞和人类诱导的多能干细胞（hiPSCs）混合在一起，随后允许它们聚集和关节成熟形成tbo（图1A）。全贴载免疫染色和清除类器官的共聚焦显微镜显示，绿色荧光蛋白（GFP）标记的人ETMR和ATRT-SHH （hETMR和hATRT-SHH）细胞在整个fbo中广泛而均匀地整合（图1B）。自动化工作流程允许在96孔板上并行生成高度均匀和可重复的tbo，在hETMR-FBO和hatrt - sh - fbo的多个tbo中，GFP信号强度的平均标准误差很低，指示肿瘤含量（图1C）。为了全面表征TBOs，我们采用免疫组织化学（IHC）检测了hETMR-和hatrt - sh -FBOs的表型，并以年龄匹配的FBOs为对照。基于lin-28同源物A （LIN28A）阳性、多层莲座、C19MC改变以及GFP免疫荧光鉴定hETMR肿瘤区域（图1D，补充图S4A-D）。对照1月龄FBOs在培养过程中（2-3月龄时为MAP2C+、SOX2 -、LIN28A -）成熟，表型以不成熟为主[LIN28A+、SRY-box转录因子2 +、微管相关蛋白2C+]。hETMR细胞在所有时间点上一致显示未成熟祖细胞标记物（LIN28A+、SOX2+和Nestin+）阳性（图1D，补充图S4A-D）。此外，很少有hETMR细胞表现出细胞质MAP2C阳性。对于hATRT-SHH，根据IHC中SWI/ snf相关基质相关动作蛋白依赖的染色质亚家族B成员1的调节因子（SMARCB1）阴性（ATRT的标志）和免疫荧光中GFP阳性（图1E，补充图S4E-F）来确定肿瘤区域。值得注意的是，hart - shh细胞sox2阳性，部分map2c阳性（图1E，补充图S4E-F）。hETMR和hATRT-SHH细胞主要表现为不成熟表型（SOX2+，少数MAP2C+细胞）。与原发肿瘤一致，它们表现出特定的特征：hETMR中C19MC扩增和多层花环，而hATRT中SMARCB1阴性。最近的研究强调了在体内观察到的ETMR[5]和ATRT[6]的肿瘤内转录异质性，这种异质性在肿瘤细胞系中没有反映出来（补充图S5）。为了评估我们的tbo是否能更好地反映原发肿瘤细胞与肿瘤球的肿瘤内异质性，我们进行了单细胞RNA测序（scRNA-seq），并将我们的数据与公开的原发肿瘤数据集相结合[5-7]。对于ETMR，我们将肿瘤细胞分为放射状胶质样（RG-like）、神经元祖细胞样（NProg-like）和神经母细胞样（Nb-like）亚组，所有亚群都出现在hETMR-FBO中（图1F，补充图S6A-B）。相比之下，肿瘤球培养在hETMR中主要表现为nprog样细胞，在mETMR中主要表现为循环rg样细胞，这表明与tbo和初级样品中观察到的转录景观不同（图1G，补充图S6C-G）。 对于hATRT-SHH，我们采用基于特征的方法，使用胎儿前脑图谱[8]的神经元特征，将hATRT-SHH细胞分为类似于胎儿放射状胶质细胞（RG）、神经元祖细胞（NProg）和神经母细胞（Nb）的亚组，并将其余细胞分类为未分化细胞（图1H，补充图S6H-I）。值得注意的是，原代和TBO肿瘤细胞在亚群中表现出平衡分布，而肿瘤球培养则表现出向nprog样状态倾斜的分布（图1I）。此外，指示神经元分化的标记基因，如statthmin 2 (STMN2)，在瘤球nb样细胞中明显缺失（Supplementary Figure S6J）。随后的细胞周期动力学分析显示，与tbo相比，肿瘤球表现出循环细胞的积累，后者表现出与初级样品相似的动力学（补充图S7）。Pearson相关分析进一步证实，与原发肿瘤和肿瘤球相比，原发肿瘤与TBO之间的相关性更高（图1J-K，补充图S8A-B），强调TBO在再现原发肿瘤转录格局方面具有更高的保真度。差异表达分析揭示了肿瘤球和tbo之间基因表达模式的显著变化（补充图S8C-D），表明神经组织环境对肿瘤细胞表型有上下文影响。利用我们的TBO模型同时宿主肿瘤和神经元细胞的独特能力，我们建立了一个细胞类型特异性药物筛选的自动化工作流程。TBO形成和发展后，于第20天开始药物治疗，第30天固定TBO进行后续分析，然后进行全挂载免疫染色、组织清除和高含量成像（图1L）。作为概念验证，我们通过评估依托opo苷对小鼠ETMR肿瘤（黄色荧光蛋白；YFP+）和神经元（MAP2C+） FBO细胞的作用，确定了依托opo苷的治疗窗口，该浓度范围最大限度地提高了抗肿瘤功效，同时最小化了神经元毒性（补充图S9）。在确定了tbo中细胞类型特异性毒性筛选的可行性后，我们接下来筛选了美国食品药品监督管理局批准的160种hetmr - fbo药物库（补充表S1），以确定新的药物脆弱性。大多数化合物对肿瘤的毒性高于对TME细胞的毒性（补充图S10）。有趣的是，我们筛选的四种高分药物（图1M），阿霉素、柔红霉素、长春新碱和阿糖胞苷，目前正在临床试验中作为治疗ETMR的新疗法进行研究[9,10]。三种具有高抗肿瘤活性和低神经毒性的候选药物——雷公藤甲素、阿霉素和柔红霉素的剂量-反应曲线验证了它们的抗肿瘤作用（减少GFP+细胞），并评估了它们对MAP2C+神经细胞的毒性（图1N-P）。值得注意的是，雷公藤甲素具有显著的抗肿瘤活性，且神经元毒性相对较低。正在进行ETMR临床研究的蒽环类药物（阿霉素和柔红霉素）的鉴定[9,10]，通过使用PERCEPTION（见方法）的独立计算分析进一步验证，预测蒽环类药物对原发性ETMR的疗效很高（补充图S11）。这一发现加强了我们筛选平台的预测有效性。总之，我们使用一种简单、自动化的共聚集方法建立了ETMR-和atrt - sh - fbo模型，与传统的肿瘤球相比，该方法能更好地概括原发肿瘤的组织学特征和转录异质性。我们的研究验证了细胞类型特异性药物筛选的方法，并确定了蒽环
{"title":"In vivo intratumoral heterogeneity in a dish: scalable forebrain organoid models of embryonal brain tumors for high-throughput personalized drug discovery","authors":"Nicole C. Riedel, Carolin Walter, Flavia W. de Faria, Lea Altendorf, Paula Aust, Carolin Göbel, Archana Verma, Annika Ballast, Ivan Bedzhov, Rajanya Roy, Daniel Münter, Erik Schüftan, Thomas K. Albert, Claudia Rössig, Pascal Johann, Barbara von Zezschwitz, Sarah Sandmann, Julian Varghese, Christian Thomas, Ulrich Schüller, Jan M. Bruder, Kornelius Kerl","doi":"10.1002/cac2.70074","DOIUrl":"10.1002/cac2.70074","url":null,"abstract":"<p>Brain tumors are the most prevalent solid tumors in pediatrics, with atypical teratoid and rhabdoid tumor (ATRT) and embryonal tumor with multilayered rosettes (ETMR) presenting particularly poor prognoses.</p><p>The development of effective therapies is hampered by the lack of in vitro models that accurately reflect the complex tumor microenvironment (TME) and intratumoral heterogeneity observed in vivo. Traditional monolayer and tumorsphere/tumoroid cultures fail to capture these critical aspects [<span>1</span>], biasing them towards proliferative cell populations that respond differently to drugs than the original tumor. Likewise, in vivo models have fundamental limitations: they lack the primate-specific chromosome 19 microRNA cluster (C19MC) driver central to ETMR [<span>2</span>], cannot capture human-specific neurotoxicity, and are impractical for scalable drug screens [<span>1, 3</span>].</p><p>To address this, we developed a scalable and reproducible tumor-forebrain-organoid (TBO) model for ETMR and ATRT sonic hedgehog (ATRT-SHH) using a novel coaggregation method, which we characterized histologically and transcriptionally, and applied to drug screening, thereby identifying new candidate therapeutics for ETMR (Supplementary File of Methods). The automated workflow ensures high reproducibility and scalability, enabling the parallel generation of thousands of TBOs for high-throughput drug screening on tumor and TME.</p><p>To integrate central nervous system embryonal tumors into forebrain organoids (FBOs), which recapitulate key developmental trends and contain comparable cell populations found in first- and second-trimester fetal brains, we modified an automated FBO model [<span>4</span>] (Supplementary Figures S1, S3). For this, we employed a coaggregation approach, which involved mixing tumor and human-induced pluripotent stem cells (hiPSCs), and subsequently allowing their aggregation and joint maturation to form TBOs (Figure 1A). Confocal microscopy of whole-mount immunostained and cleared organoids revealed a broad and uniform integration of green fluorescent protein (GFP)-tagged human ETMR and ATRT-SHH (hETMR and hATRT-SHH) cells throughout FBOs (Figure 1B). The automated workflow allowed for the parallel generation of highly uniform and reproducible TBOs in 96-well plates, with low-standard error of the mean for the GFP signal intensity, indicative for tumor content, across multiple TBOs for both hETMR-FBO and hATRT-SHH-FBO (Figure 1C).</p><p>To comprehensively characterize TBOs, we employed immunohistochemistry (IHC) to examine the phenotype of hETMR- and hATRT-SHH-FBOs, with age-matched FBOs as controls. hETMR tumor areas were identified based on lin-28 homolog A (LIN28A) positivity, multilayered rosettes, and C19MC alterations, along with GFP immunofluorescence (Figure 1D, Supplementary Figure S4A-D). Control 1-month aged FBOs exhibited a predominantly immature phenotype [LIN28A<sup>+</sup>, SRY-box transcription factor 2 (","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1670-1675"},"PeriodicalIF":24.9,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145430387","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：