Cancer research最新文献

{"title":"Targeting TUT1 Depletes Tri-snRNP Pools to Suppress Splicing and Inhibit Pancreatic Cancer Cell Survival","authors":"Ziwei Guo, Junran Huang, Zhi J. Lu, Yongsheng Shi, Charles J. David, Mo Chen","doi":"10.1158/0008-5472.can-24-2563","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2563","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and lacks effective therapeutic options. Cancer cells frequently become more dependent on splicing factors than normal cells due to increased rates of transcription. Terminal uridylyltransferase 1 (TUT1) is a specific terminal uridylyltransferase for U6 small nuclear RNA (snRNA), which plays a catalytic role in the spliceosome. Here, we found that TUT1 was required for the survival of PDAC cells but not for normal pancreatic cells. In PDAC cells, the uridylylation activity of TUT1 promoted tri-snRNP assembly by facilitating the binding of LSM proteins to U6 snRNA and subsequent tri-snRNP assembly. PDAC cells required higher amounts of tri-snRNP to efficiently splice pre-mRNA with weak splice sites to support the high transcriptional output. Depletion of TUT1 in PDAC cells resulted in inefficient splicing of exons in a group of highly expressed RNAs containing weak splice sites, thereby resulting in the collapse of an mRNA processing circuit and consequently dysregulating splicing required by PDAC cells. Overall, this study unveiled an interesting function of TUT1 in regulating splicing by modulating tri-snRNP levels and demonstrated a distinct mechanism underlying splicing addiction in pancreatic cancer cells.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"87 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression","authors":"Ran Chen, Cuihong Ma, Haoran Qian, Xinyu Xie, Yuxue Zhang, Dayun Lu, Shunjie Hu, Mao Zhang, Fen Liu, Yunhao Zou, Qiang Gao, Hu Zhou, Hailong Liu, Moubin Lin, Gaoxiang Ge, Daming Gao","doi":"10.1158/0008-5472.can-24-2097","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2097","url":null,"abstract":"Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy affecting the liver and biliary system. Enhanced understanding of the pathogenic mechanisms underlying iCCA tumorigenesis and the discovery of appropriate therapeutic targets are imperative to improve patient outcomes. Here, we investigated the functions and regulations of solute carrier family 16 member 3 (SLC16A3), which has been reported to be a biomarker of poor prognosis in iCCA. High SLC16A3 expression was enriched in KRAS-mutated iCCA tumors, and mutant KRAS elevated SLC16A3 expression via the PI3K/AKT/mTORC1/HIF1α pathway. SLC16A3 not only enhanced glycolysis but also induced epigenetic reprogramming to regulate iCCA progression. Phosphorylation of SLC16A3 at S436 (p-S436) was vital for its oncogenic function and was linked to iCCA progression. Casein kinase 2 (CK2) directly phosphorylated SLC16A3 at S436, and CK2 inhibition with CX-4945 (silmitasertib) reduced the growth of KRAS-mutated iCCA tumor xenografts and patient-derived organoids. Together, this study provides valuable insights into the diverse functions of SLC16A3 in iCCA and comprehensively elucidates the upstream regulatory mechanisms, providing potential therapeutic strategies for iCCA patients with KRAS mutations.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"38 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accumulation of CD38 in Hybrid Epithelial/Mesenchymal Cells Promotes Immune Remodeling and Metastasis in Breast Cancer","authors":"Tanvi H. Visal, Recep Bayraktar, Petra den Hollander, Michael A. Attathikhun, Tieling Zhou, Jing Wang, Li Shen, Corina-Elena Minciuna, Meng Chen, Elizve Barrientos-Toro, Harsh Batra, Maria Gabriela Raso, Fei Yang, Edwin R. Parra, Aysegul A. Sahin, George A. Calin, Sendurai A. Mani","doi":"10.1158/0008-5472.can-24-0400","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0400","url":null,"abstract":"Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer. The epithelial-to-mesenchymal transition is a nonbinary process in the metastatic cascade that generates tumor cells with both epithelial and mesenchymal traits known as hybrid EM cells. Recent studies have elucidated the enhanced metastatic potential of cancers featuring the hybrid EM phenotype, highlighting the need to uncover molecular drivers and targetable vulnerabilities of the hybrid EM state. Here, we discovered that hybrid EM breast tumors are enriched in CD38, an immunosuppressive molecule associated with worse clinical outcomes in liquid malignancies. Altering CD38 expression in tumor cell impacted migratory, invasive, and metastatic capabilities of hybrid EM cells. Abrogation of CD38 expression stimulated an antitumor immune response, thereby preventing the generation of an immunosuppressive microenvironment in hybrid EM tumors. CD38 levels positively correlated with PD-L1 expression in samples from patients with TNBC. Moreover, targeting CD38 potentiated the activity of anti–PD-L1, eliciting strong antitumor immunity, with reduced tumor growth in hybrid EM models. Overall, this research exposes upregulation of CD38 as a specific survival strategy utilized by hybrid EM breast tumors to suppress immune cell activity and sustain metastasis, with strong implications in other carcinomas that have hybrid EM properties. Significance: Hybrid cells co-featuring epithelial and mesenchymal traits in triple-negative breast cancer express elevated levels of CD38 to induce immunosuppression and metastasis, indicating CD38 inhibition as potential strategy for treating breast cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"34 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNHG17 Reprograms Energy Metabolism of Breast Cancer by Activating Mitochondrial DNAs Transcription.","authors":"Lin Gao, Jingyi Huang, Jinquan Xia, Pan Zhao, Shaowei Dong, Wei Jiang, Qianqian Zhou, Zhenglei Xu, Hui Luo, Wenbin Zhou, Jichao Sun, Guangsuo Wang, Qingshan Geng, Jigang Wang, Chang Zou","doi":"10.1158/0008-5472.CAN-24-1271","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-1271","url":null,"abstract":"<p><p>In most solid tumors, cellular energy metabolism is primarily dominated by aerobic glycolysis, which fulfills the high demand for biomacromolecules at the expense of reduced ATP production efficiency. Elucidation of the mechanisms by which rapidly proliferating malignant cells acquire sufficient energy in this state of inefficient ATP production from glycolysis could enable development of metabolism targeted therapeutic strategies. In this study, we observed a significant association between elevated expression levels of the long non-coding RNA (lncRNA) SNHG17 and unfavorable prognosis in breast cancer (BCa). SNHG17 promoted BCa cell proliferation by augmenting mitochondrial ATP production. Mechanistically, SNHG17 directly interacted with the p65 subunit of NF-κB and phosphorylated p65 at the threonine 505 site. SNHG17 bound to p65 at its truncated loop2 site, recruited p65 to mitochondria, and co-regulated the transcriptional activation of mitochondrial DNA to promote ATP production. Accordingly, targeting SNHG17 with an anti-sense oligonucleotide (ASO) significantly reduced BCa tumor growth both in vitro and in vivo. Overall, these results established a role for SNHG17 in promoting BCa progression by increasing ATP production and provided insight into the reprogramming of energy metabolism in solid tumors.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMAD4 and KRAS Status Shape Cancer Cell-Stromal Crosstalk and Therapeutic Response in Pancreatic Cancer.","authors":"Eloise G Lloyd, Muntadher Jihad, Judhell S Manansala, Wenlong Li, Priscilla S W Cheng, Gianluca Mucciolo, Marta Zaccaria, Sara Pinto Teles, Joaquín Araos Henríquez, Sneha Harish, Rebecca Brais, Sally Ashworth, Weike Luo, Paul M Johnson, Lisa Veghini, Mireia Vallespinos, Vincenzo Corbo, Giulia Biffi","doi":"10.1158/0008-5472.CAN-24-2330","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2330","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on pre-clinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase understanding of malignant cell-stroma crosstalk in PDAC. Here, we used single-cell RNA-sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V in which Smad4 was wild-type or deleted. KrasG12D Smad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared to KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype impacts cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting ARPC1B Overcomes Immune Checkpoint Inhibitor Resistance in Glioblastoma by Reversing Pro-tumorigenic Macrophage Polarization.","authors":"Tianqi Liu, Tao Sun, Xin Chen, Jianqi Wu, Xiaoqian Sun, Xing Liu, Haixu Yan, Qiang Fu, Zirong Fan, Xiangyu Wang, Peng Cheng, Wen Cheng, Anhua Wu","doi":"10.1158/0008-5472.CAN-24-2286","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2286","url":null,"abstract":"<p><p>Immunotherapy has elicited significant improvements in outcomes for patients with several tumor types. However, the immunosuppressive microenvironment in glioblastoma restricts the therapeutic efficacy of immune checkpoint blockade (ICB). In this study, we investigated which components of the immune microenvironment contribute to ICB failure in glioblastoma to elucidate the underlying causes of immunotherapeutic resistance. Macrophages were identified as a main contributor to ICB resistance. Expression of ARPC1B, a regulatory subunit of the Arp2/3 complex, was elevated in glioblastoma and correlated with macrophage enrichment and prognosis. ARPC1B in tumor cells increased STAT1 expression and subsequent IL10 production, which induced a pro-tumorigenic macrophage state. Mechanistically, ARPC1B inhibited the ubiquitination and degradation of STAT1 by preventing the E3 ubiquitin ligase NEDD4L from binding to STAT1 and by supporting the interaction between STAT1 and the deubiquitinase USP7. Inhibiting ARPC1B reshaped the immunosuppressive microenvironment and increased the efficacy of ICB in glioblastoma models. This study highlights the important role of ARPC1B in macrophage-mediated immunosuppression and proposes a combination treatment regimen for glioblastoma immunotherapy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multipotent PROX1+ Tumor Stem/Progenitor Cell Population Emerges During Intestinal Tumorigenesis and Mediates Radioresistance in Colorectal Cancer.","authors":"Pauliina Kallio, Cinzia Bessone, Fatemeh Seyednasrollah, Jefim Brodkin, Marika Lassila, Jenny Högström, Alejandra González-Loyola, Tatiana V Petrova, Caj Haglund, Kari Alitalo","doi":"10.1158/0008-5472.CAN-23-1851","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-1851","url":null,"abstract":"<p><p>Colorectal carcinoma (CRC) progression is associated with an increase in PROX1+ tumor cells, which exhibit features of CRC stem cells and contribute to metastasis. Here, we aimed to provide a better understanding to the function of PROX1+ cells in CRC, investigating their progeny and their role in therapy resistance. PROX1+ cells in intestinal adenomas of ApcMin/+ mice expressed intestinal epithelial and CRC stem cell markers, and cells with high PROX1 expression could both self-renew tumor stem/progenitor cells and contribute to differentiated tumor cells. Most PROX1-lineage traced tumor cells were stem/progenitor cells, which can supply cells to multiple intestinal tumor cell lineages, whereas most lineage-traced LGR5+ tumor cells were enterocytes, indicating that PROX1+ and LGR5+ tumor stem cells have distinct differentiation programs. Although the PROX1+ tumor cells proliferated slower than PROX1- cells, irradiation increased the proportion of PROX1+ cells in human CRC cell lines, patient-derived organoids, and tumor xenografts. Furthermore, transcripts related to DNA damage repair (DDR) were enriched in PROX1+ vs. PROX1- cells in adenomas and in CRC tumor cells from patients. Experiments with PROX1 silencing and overexpression indicated that PROX1 expression enhances CRC cell colony formation following irradiation. PROX1 interacted with DDR proteins, including components of non-homologous end-joining (NHEJ) and base excision repair, and inhibition of NHEJ repair led to a decreased proportion of PROX1+ cells following irradiation. In conclusion, PROX1+ cells are irradiation-resistant tumor stem/progenitor cells capable of self-renewal and differentiation. DDR inhibitors could represent a strategy to target the treatment-resistant PROX1+ tumor stem cells.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Lean, Obese, and Weight Loss Models Reveals TREM2 Deficiency Attenuates Breast Cancer Growth Uniquely in Lean Mice and Alters Clonal T Cell Populations","authors":"Elysa W. Pierro, Matthew A. Cottam, Hanbing An, Brian D. Lehmann, Jennifer A. Pietenpol, Kathryn E. Wellen, Liza Makowski, Jeffrey C. Rathmell, Barbara Fingleton, Alyssa H. Hasty","doi":"10.1158/0008-5472.can-24-3511","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3511","url":null,"abstract":"Obesity is an established risk factor for breast cancer development and poor prognosis. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression, and TREM2, a transmembrane receptor expressed on macrophages in adipose tissue and tumors, is an emerging therapeutic target for cancer. A better understanding of the mechanisms for the obesity-breast cancer association and the potential benefits of weight loss could help inform treatment strategies. Here, we utilized lean, obese, and weight loss mouse models to examine the impacts of TREM2 deficiency (Trem2+/+ and Trem2-/-) on postmenopausal breast cancer depending on weight history conditions. Trem2 deficiency constrained tumor growth in lean, but not obese or weight loss, mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed differences in the immune landscapes across the different models. Tumors of lean Trem2-/- mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adj of the same mouse. Finally, anti-PD-1 therapy restricted tumor growth in lean and weight loss, but not obese, mice. These findings indicate that weight history could impact the efficacy of TREM2 inhibition in postmenopausal breast cancer. The reported immunological interactions between tumors and the surrounding adipose tissue highlight significant differences under obese and weight loss conditions.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"14 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BEEx Is an Open-Source Tool That Evaluates Batch Effects in Medical Images to Enable Multicenter Studies.","authors":"Yuxin Wu, Xiongjun Xu, Yuan Cheng, Xiuming Zhang, Fanxi Liu, Zhenhui Li, Lei Hu, Anant Madabhushi, Peng Gao, Zaiyi Liu, Cheng Lu","doi":"10.1158/0008-5472.CAN-23-3846","DOIUrl":"10.1158/0008-5472.CAN-23-3846","url":null,"abstract":"<p><p>The batch effect is a nonbiological variation that arises from technical differences across different batches of data during the data generation process for acquisition-related reasons, such as collection of images at different sites or using different scanners. This phenomenon can affect the robustness and generalizability of computational pathology- or radiology-based cancer diagnostic models, especially in multicenter studies. To address this issue, we developed an open-source platform, Batch Effect Explorer (BEEx), that is designed to qualitatively and quantitatively determine whether batch effects exist among medical image datasets from different sites. A suite of tools was incorporated into BEEx that provide visualization and quantitative metrics based on intensity, gradient, and texture features to allow users to determine whether there are any image variables or combinations of variables that can distinguish datasets from different sites in an unsupervised manner. BEEx was designed to support various medical imaging techniques, including microscopy and radiology. Four use cases clearly demonstrated the ability of BEEx to identify batch effects and validated the effectiveness of rectification methods for batch effect reduction. Overall, BEEx is a scalable and versatile framework designed to read, process, and analyze a wide range of medical images to facilitate the identification and mitigation of batch effects, which can enhance the reliability and validity of image-based studies. Significance: BEEx is a prescreening tool for image-based analyses that allows researchers to evaluate batch effects in multicenter studies and determine their origin and magnitude to facilitate development of accurate AI-based cancer models.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"218-230"},"PeriodicalIF":12.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805805","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}

{"title":"FOXR2 Targets LHX6+/DLX+ Neural Lineages to Drive Central Nervous System Neuroblastoma.","authors":"Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Michael McNicholas, Steven Hébert, Adam Ptack, Damien Faury, Jessica W Tsai, Andrey Korshunov, Timothy N Phoenix, Benjamin Ellezam, David T W Jones, Michael D Taylor, Pratiti Bandopadhayay, Manav Pathania, Nada Jabado, Claudia L Kleinman","doi":"10.1158/0008-5472.CAN-24-2248","DOIUrl":"10.1158/0008-5472.CAN-24-2248","url":null,"abstract":"<p><p>Central nervous system neuroblastoma with forkhead box R2 (FOXR2) activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal Foxr2 targeting to the ganglionic eminences in mice induced postnatal cortical tumors recapitulating human NB-FOXR2-specific molecular signatures. Profiling of FOXR2 binding on chromatin in murine models revealed an association with ETS transcriptional networks, as well as direct binding of FOXR2 at key transcription factors that coordinate initiation of gliogenesis. These data indicate that NB-FOXR2 tumors originate from LHX6+/DLX+ interneuron lineages, a lineage of origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics. Significance: Profiling the developing brain enabled rationally guided modeling of FOXR2-activated CNS neuroblastoma, providing a strategy to overcome the heterogeneous origins of pediatric brain tumors that hamper tumor modeling and therapy development. See related commentary by Orr, p. 195.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"231-250"},"PeriodicalIF":12.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566526","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}