Pub Date : 2025-12-29DOI: 10.1158/0008-5472.CAN-24-2648
Julia Yemelyanenko, Jinhyuk Bhin, Eline van der Burg, Anne Paulien Drenth, Jessica K Lee, Catrin Lutz, Lea Dörner, Ellen Wientjens, Sjoerd Klarenbeek, Ji-Ying Song, Hyeonjin Moon, Stefano Annunziato, Natalie Proost, Bjørn Siteur, Jeffrey S Ross, Marieke van de Ven, Olaf van Tellingen, Shridar Ganesan, Lodewyk F A Wessels, Daniel Zingg, Jos Jonkers
Genomic alterations affecting components of the fibroblast growth factor (FGF) signaling axis can trigger aberrant pathway activation and tumor development. Genomic truncation of the FGF receptor 2 (FGFR2) exon 18 (E18) disrupts the FGFR2 carboxy-terminal tail (C-tail), acting as a potent driver alteration across multiple tumor types. Here, we analyzed human oncogenomic datasets to reveal that E18 truncations are similarly prevalent in FGFR3, an FGFR2 paralog. FGFR3 E18 truncations primarily occurred due to rearrangements (REs) that involve transforming acidic coiled-coil containing protein 3 (TACC3), resulting in FGFR3ΔE18-TACC3 gene fusions. In contrast to E18-truncated FGFR2, functional in vitro and in vivo examination of Fgfr3 variants demonstrated that the truncation of Fgfr3 E18 is insufficient to promote oncogenic activity in cell lines or in the lungs and mammary glands of mice. Only the combination of an Fgfr3 E18 truncation with a RE partner gene that encodes a receptor-dimerizing domain resulted in the development of tumors, which were sensitive to FGFR inhibition. Overall, these findings suggest that patients with cancers that are positive for rearranged FGFR3 resulting in E18 truncation and a fusion to dimerizing partners should be considered for FGFR-targeted therapies.
{"title":"C-terminal Truncation and Fusion Partner Determine Oncogenicity of FGFR3.","authors":"Julia Yemelyanenko, Jinhyuk Bhin, Eline van der Burg, Anne Paulien Drenth, Jessica K Lee, Catrin Lutz, Lea Dörner, Ellen Wientjens, Sjoerd Klarenbeek, Ji-Ying Song, Hyeonjin Moon, Stefano Annunziato, Natalie Proost, Bjørn Siteur, Jeffrey S Ross, Marieke van de Ven, Olaf van Tellingen, Shridar Ganesan, Lodewyk F A Wessels, Daniel Zingg, Jos Jonkers","doi":"10.1158/0008-5472.CAN-24-2648","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2648","url":null,"abstract":"<p><p>Genomic alterations affecting components of the fibroblast growth factor (FGF) signaling axis can trigger aberrant pathway activation and tumor development. Genomic truncation of the FGF receptor 2 (FGFR2) exon 18 (E18) disrupts the FGFR2 carboxy-terminal tail (C-tail), acting as a potent driver alteration across multiple tumor types. Here, we analyzed human oncogenomic datasets to reveal that E18 truncations are similarly prevalent in FGFR3, an FGFR2 paralog. FGFR3 E18 truncations primarily occurred due to rearrangements (REs) that involve transforming acidic coiled-coil containing protein 3 (TACC3), resulting in FGFR3ΔE18-TACC3 gene fusions. In contrast to E18-truncated FGFR2, functional in vitro and in vivo examination of Fgfr3 variants demonstrated that the truncation of Fgfr3 E18 is insufficient to promote oncogenic activity in cell lines or in the lungs and mammary glands of mice. Only the combination of an Fgfr3 E18 truncation with a RE partner gene that encodes a receptor-dimerizing domain resulted in the development of tumors, which were sensitive to FGFR inhibition. Overall, these findings suggest that patients with cancers that are positive for rearranged FGFR3 resulting in E18 truncation and a fusion to dimerizing partners should be considered for FGFR-targeted therapies.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854029","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}
Peripheral nerve invasion (PNI) is an early and decisive step in gallbladder cancer (GBC) progression that strongly predicts poor post-surgical outcome. The tumor-neuron interactions that drive PNI could represent potential targets and biomarkers to improve treatment of GBC. Here, we demonstrated that GBC provoked necroptosis of neurons to enable PNI. GBC cells transferred extracellular vesicles (EVs) containing O-GlcNAcase (OGA) to neurons, which activated RIPK1-dependent necroptosis. Mechanistically, EV-derived OGA suppressed RIPK1 glycosylation while enhancing its phosphorylation, thereby activating the RIPK1/RIPK3/MLKL axis to trigger neuronal necroptosis. Subsequent neuronal release of HMGB1 engaged RAGE on GBC cells, establishing a loop that accelerated PNI. Moreover, the RAGE antagonist FPS-ZM1 synergized with gemcitabine to suppress tumor progression. Collectively, these findings uncover an EV-mediated crosstalk between GBC cells and neurons in which RIPK1-dependent necroptosis and its effector HMGB1 drive PNI, positioning the HMGB1-RAGE axis as a tractable therapeutic target.
{"title":"Extracellular Vesicle-Mediated O-GlcNAcase Transfer Drives Neuronal Necroptosis to Facilitate Gallbladder Cancer Perineural Invasion.","authors":"Jing-Wei Zhao, Jia Yun Zhu, Ziyi Yang, Yang-Yang Zhai, Cheng Zhao, Zhichao Lu, Danyang Shen, Qiu-Yi Tang, Xiaoling Song, Lin Jiang, Wen-Ting Dai, Ya-Xuan Wang, Yidi Zhu, Liu-Qing Shi, Runfa Bao, Zhimin Geng, Ziheng Wang, Shi-Lei Liu, Wei Gong","doi":"10.1158/0008-5472.CAN-25-2237","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-2237","url":null,"abstract":"<p><p>Peripheral nerve invasion (PNI) is an early and decisive step in gallbladder cancer (GBC) progression that strongly predicts poor post-surgical outcome. The tumor-neuron interactions that drive PNI could represent potential targets and biomarkers to improve treatment of GBC. Here, we demonstrated that GBC provoked necroptosis of neurons to enable PNI. GBC cells transferred extracellular vesicles (EVs) containing O-GlcNAcase (OGA) to neurons, which activated RIPK1-dependent necroptosis. Mechanistically, EV-derived OGA suppressed RIPK1 glycosylation while enhancing its phosphorylation, thereby activating the RIPK1/RIPK3/MLKL axis to trigger neuronal necroptosis. Subsequent neuronal release of HMGB1 engaged RAGE on GBC cells, establishing a loop that accelerated PNI. Moreover, the RAGE antagonist FPS-ZM1 synergized with gemcitabine to suppress tumor progression. Collectively, these findings uncover an EV-mediated crosstalk between GBC cells and neurons in which RIPK1-dependent necroptosis and its effector HMGB1 drive PNI, positioning the HMGB1-RAGE axis as a tractable therapeutic target.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1158/0008-5472.can-24-1938
Dina ElHarouni, Rosa Hernansaiz-Ballesteros, Heike Peterziel, Gnana Prakash Balasubramanian, Christopher Previti, Kathrin Schramm, Mirjam Blattner-Johnson, Rolf Kabbe, Barbara C. Jones, Sina Oppermann, David T.W. Jones, Stefan M. Pfister, Olaf Witt, Julio Saez-Rodriguez, Ina Oehme, Natalie Jäger, Matthias Schlesner
Cure rates for childhood malignancies using established therapy protocols have increased to an average of 80% but have reached a plateau. Moreover, survival rates are particularly low for some pediatric tumors—such as high-risk group 3 medulloblastomas, osteosarcomas, Ewing sarcomas, high-risk neuroblastomas, and high-grade gliomas—and dismal for patients with relapsed malignancies. A functional drug response profiling platform for pediatric solid and brain tumors has been established within the INFORM program to identify patient-specific vulnerabilities and biomarkers and to unravel molecular mechanisms associated with drug response profiles for clinical translation. In this study, we performed a multiomics analysis using drug sensitivity profiles, as well as genomic and transcriptomic data, of 81 pediatric solid tumor samples. The integrative analysis suggested two multiomics signatures associated with drug sensitivity. One signature distinguished neuroblastoma samples with sensitivity to navitoclax, a BCL2 family inhibitor. A second signature was specific to a subset of Wilms tumors harboring the SIX1 (Q177R) hotspot mutation that displayed high expression of MGAM, PTPN14, STAT4, and KDM2B and high sensitivity to MEK inhibitors. A patient-specific causal interaction network analysis suggested possible molecular interactions between MEK inhibitors and the SIX1 mutation in Wilms tumor samples. In conclusion, the integration of drug sensitivity profiling and multiomics data revealed potential biomarkers that may be associated with drug sensitivity in pediatric solid tumors. Patient-specific causal interaction network analysis further elucidated the interaction between inhibitors and signature biomarkers, providing insights that may inform clinical translation. Significance: The combination of multiomics analysis and drug sensitivity profiling identified two signatures related to drug sensitivity in pediatric solid tumors, contributing to the advancement of functional precision medicine and personalized treatment strategies. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI .
{"title":"Integrative Multiomics and Drug Sensitivity Profiling Reveal Potential Biomarkers and Therapeutic Strategies in Pediatric Solid Tumors","authors":"Dina ElHarouni, Rosa Hernansaiz-Ballesteros, Heike Peterziel, Gnana Prakash Balasubramanian, Christopher Previti, Kathrin Schramm, Mirjam Blattner-Johnson, Rolf Kabbe, Barbara C. Jones, Sina Oppermann, David T.W. Jones, Stefan M. Pfister, Olaf Witt, Julio Saez-Rodriguez, Ina Oehme, Natalie Jäger, Matthias Schlesner","doi":"10.1158/0008-5472.can-24-1938","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1938","url":null,"abstract":"Cure rates for childhood malignancies using established therapy protocols have increased to an average of 80% but have reached a plateau. Moreover, survival rates are particularly low for some pediatric tumors—such as high-risk group 3 medulloblastomas, osteosarcomas, Ewing sarcomas, high-risk neuroblastomas, and high-grade gliomas—and dismal for patients with relapsed malignancies. A functional drug response profiling platform for pediatric solid and brain tumors has been established within the INFORM program to identify patient-specific vulnerabilities and biomarkers and to unravel molecular mechanisms associated with drug response profiles for clinical translation. In this study, we performed a multiomics analysis using drug sensitivity profiles, as well as genomic and transcriptomic data, of 81 pediatric solid tumor samples. The integrative analysis suggested two multiomics signatures associated with drug sensitivity. One signature distinguished neuroblastoma samples with sensitivity to navitoclax, a BCL2 family inhibitor. A second signature was specific to a subset of Wilms tumors harboring the SIX1 (Q177R) hotspot mutation that displayed high expression of MGAM, PTPN14, STAT4, and KDM2B and high sensitivity to MEK inhibitors. A patient-specific causal interaction network analysis suggested possible molecular interactions between MEK inhibitors and the SIX1 mutation in Wilms tumor samples. In conclusion, the integration of drug sensitivity profiling and multiomics data revealed potential biomarkers that may be associated with drug sensitivity in pediatric solid tumors. Patient-specific causal interaction network analysis further elucidated the interaction between inhibitors and signature biomarkers, providing insights that may inform clinical translation. Significance: The combination of multiomics analysis and drug sensitivity profiling identified two signatures related to drug sensitivity in pediatric solid tumors, contributing to the advancement of functional precision medicine and personalized treatment strategies. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI .","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"27 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1158/0008-5472.can-25-1594
Sandhya Prabhakaran, Chandler D. Gatenbee, Mark Robertson-Tessi, Zarifa Gahramanli Ozturk, Theresa A. Boyle, Jhanelle E. Gray, Scott J. Antonia, Robert A. Gatenby, Amer A. Beg, Alexander R. A. Anderson
Multiplexed imaging of tissues is an approach that holds promise for improving early detection, diagnosis, and treatment of cancer. Here, we investigated multiplexed histological images of paired pre- and on-treatment samples from nine patients with immunotherapy-refractory non-small cell lung cancer (NSCLC) treated with an oral HDAC inhibitor (vorinostat) combined with a PD-1 inhibitor (pembrolizumab). Patient responses comprised of either stable disease (SD) or progressive disease (PD). An extensive multiplexed-image analysis pipeline involving both cell segmentation and quadrats, coupled with spatial statistics, machine learning, and deep learning was built to analyze the spatial and temporal features that predict disease progression and identify potential clinical biomarkers. Distinct spatial immune ecologies existed between SD and PD patients, and tumors from PD patients were already characterized by an immune-suppressive environment prior to treatment. Finally, the learned spatial ecologies predicted disease progression better than PD-L1 status alone, suggesting these ecologies could be used as potential companion biomarkers with PD-L1 in NSCLC. These findings will be investigated in a larger-cohort study generated from an ongoing clinical trial (NCT02638090) that includes a wider range of responses including complete and partial responders. Together, this study developed a computational infrastructure for analyzing multiplex imaging to predict immunotherapy response in NSCLC, which can potentially be generalized to any type of cancer.
{"title":"Distinct Tumor-Immune Ecologies in Lung Cancer Patients Predict Progression and Define a Clinical Biomarker of Therapy Response","authors":"Sandhya Prabhakaran, Chandler D. Gatenbee, Mark Robertson-Tessi, Zarifa Gahramanli Ozturk, Theresa A. Boyle, Jhanelle E. Gray, Scott J. Antonia, Robert A. Gatenby, Amer A. Beg, Alexander R. A. Anderson","doi":"10.1158/0008-5472.can-25-1594","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1594","url":null,"abstract":"Multiplexed imaging of tissues is an approach that holds promise for improving early detection, diagnosis, and treatment of cancer. Here, we investigated multiplexed histological images of paired pre- and on-treatment samples from nine patients with immunotherapy-refractory non-small cell lung cancer (NSCLC) treated with an oral HDAC inhibitor (vorinostat) combined with a PD-1 inhibitor (pembrolizumab). Patient responses comprised of either stable disease (SD) or progressive disease (PD). An extensive multiplexed-image analysis pipeline involving both cell segmentation and quadrats, coupled with spatial statistics, machine learning, and deep learning was built to analyze the spatial and temporal features that predict disease progression and identify potential clinical biomarkers. Distinct spatial immune ecologies existed between SD and PD patients, and tumors from PD patients were already characterized by an immune-suppressive environment prior to treatment. Finally, the learned spatial ecologies predicted disease progression better than PD-L1 status alone, suggesting these ecologies could be used as potential companion biomarkers with PD-L1 in NSCLC. These findings will be investigated in a larger-cohort study generated from an ongoing clinical trial (NCT02638090) that includes a wider range of responses including complete and partial responders. Together, this study developed a computational infrastructure for analyzing multiplex imaging to predict immunotherapy response in NSCLC, which can potentially be generalized to any type of cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"361 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785813","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}
Tumor senescence is a critical mechanism underlying tumor progression and recurrence. A better understanding of how pre-metastatic circulating tumor cells (CTCs) exploit senescence to survive in the blood stream could help reveal vulnerabilities for therapeutic intervention. Using patient-derived melanoma CTC lines and xenograft models, we identified a role for the cytoskeletal regulator cortactin in mTOR/p53-dependent senescence. Cortactin localized to Rab7-positive endosomes and maintained late-endosomal homeostasis. Depletion of cortactin induced aberrant endosomal aggregates with mTOR accumulation and hyperactivation, subsequently leading to p53 activation, G0/G1 arrest, and cellular senescence. This oncogene-induced senescence (OIS) was characterized by induction of the senescence-associated secretory phenotype and β-galactosidase (SA-β-gal), loss of Ki-67 and lamin B1, and elevated mitochondrial reactive oxygen species (mtROS). Notably, a positive feedback loop between p53 and mtROS was essential for maintaining stable senescence in CTCs. Clinically, the proportion of SA-β-gal-positive senescent CTCs was significantly correlated with therapeutic resistance and disease progression in a prospective cohort of melanoma patients. A sequential strategy using cortactin depletion followed by an anti-Bcl-xL senolytic eliminated the persistent CTCs and suppressed blood-borne metastasis. Thus, this study uncovered a unique senescent CTC subpopulation regulated by a cortactin/mTOR/p53/mtROS axis that can be targeted to suppress metastatic progression of melanoma.
{"title":"Cortactin Suppresses mTOR-Dependent Senescence in Circulating Tumor Cells","authors":"Jianyang Hu, Binyu Zhang, Junhao Chen, Guanyin Huang, Mao Zhao, Hongchao Zhou, Fan Yang, Ke Liu, Shuqian Zheng, Haoyuan Tan, Xuefei Liu, Jialing Liu, Hailiang Hu, Luhua Wang, Jianglin Zhang, Lingyun Dai, Qingfeng Chen, Xinghua Pan, Hongchang Li, Hao Yu, Weinan Guo, Xin Hong","doi":"10.1158/0008-5472.can-25-1175","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1175","url":null,"abstract":"Tumor senescence is a critical mechanism underlying tumor progression and recurrence. A better understanding of how pre-metastatic circulating tumor cells (CTCs) exploit senescence to survive in the blood stream could help reveal vulnerabilities for therapeutic intervention. Using patient-derived melanoma CTC lines and xenograft models, we identified a role for the cytoskeletal regulator cortactin in mTOR/p53-dependent senescence. Cortactin localized to Rab7-positive endosomes and maintained late-endosomal homeostasis. Depletion of cortactin induced aberrant endosomal aggregates with mTOR accumulation and hyperactivation, subsequently leading to p53 activation, G0/G1 arrest, and cellular senescence. This oncogene-induced senescence (OIS) was characterized by induction of the senescence-associated secretory phenotype and β-galactosidase (SA-β-gal), loss of Ki-67 and lamin B1, and elevated mitochondrial reactive oxygen species (mtROS). Notably, a positive feedback loop between p53 and mtROS was essential for maintaining stable senescence in CTCs. Clinically, the proportion of SA-β-gal-positive senescent CTCs was significantly correlated with therapeutic resistance and disease progression in a prospective cohort of melanoma patients. A sequential strategy using cortactin depletion followed by an anti-Bcl-xL senolytic eliminated the persistent CTCs and suppressed blood-borne metastasis. Thus, this study uncovered a unique senescent CTC subpopulation regulated by a cortactin/mTOR/p53/mtROS axis that can be targeted to suppress metastatic progression of melanoma.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"111 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1158/0008-5472.can-25-1697
Emily Greene, Natalie K. Horvat, Deon Bryant. Doxie, Vaunita Cohen. Parihar, Jayden Kim, Cameron J. Herting, Erin E. Grundy, Ayana T. Ruffin, Alyssa M. Krasinskas, Shishir K. Maithel, Juan M. Sarmiento, Mihir M. Shah, Mohammad Y. Zaidi, Maria Diab, Olatunji B. Alese, Kavita Dhodapkar, Haydn T. Kissick, Bassel F. El-Rayes, Chrystal M. Paulos, Gregory B. Lesinski
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor type with poor patient outcomes. Most patients present with metastatic disease, which generally has reduced immune infiltration compared to primary tumors. Further work to elucidate the specific cellular features of metastatic PDAC is needed to guide the development of future immunotherapy strategies. Here, we investigated the hypothesis that PDAC tumors harbor distinct immunologic and stromal features depending on their anatomical site. Multiplex immunohistochemistry (mIHC), spatial analysis, and single-cell mass cytometry (CyTOF) uncovered dominant immune and stromal cell populations in tumors derived from 27 primary and 26 liver metastases. Metastatic liver tumors from PDAC patients contained reduced T cell infiltration, fibroblast populations, and collagen accumulation than primary lesions, while CD68+ cells, often co-expressing CCR2, were more abundant. Spatial analyses revealed distinct immune cell communities in primary and metastatic PDAC, whereby CK19+ cells clustered differentially with α-SMA+, CD3+, and CD68+ cells, depending on the tumor site. When comparing tumor-associated regions, the proportion of peritumoral CK19- cells remained consistent, but their composition varied by disease site. CD8+ T cells were significantly less frequent in metastatic tumors, while both CD4+ and CD8+ T cells present in primary tumors expressed more transcription factors (TFs) associated with suppressive properties, including FoxP3 and RORγt. CyTOF revealed that T cells co-expressed multiple inhibitory checkpoint receptors, most notably LAG-3 and PD-1. This report reveals that primary and metastatic tumors from PDAC patients harbor vastly distinct immunologic and stromal features at the protein level.
{"title":"High-Dimensional Protein Analysis Uncovers Distinct Immunological and Stromal Features in Primary and Metastatic Pancreatic Ductal Adenocarcinoma","authors":"Emily Greene, Natalie K. Horvat, Deon Bryant. Doxie, Vaunita Cohen. Parihar, Jayden Kim, Cameron J. Herting, Erin E. Grundy, Ayana T. Ruffin, Alyssa M. Krasinskas, Shishir K. Maithel, Juan M. Sarmiento, Mihir M. Shah, Mohammad Y. Zaidi, Maria Diab, Olatunji B. Alese, Kavita Dhodapkar, Haydn T. Kissick, Bassel F. El-Rayes, Chrystal M. Paulos, Gregory B. Lesinski","doi":"10.1158/0008-5472.can-25-1697","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1697","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor type with poor patient outcomes. Most patients present with metastatic disease, which generally has reduced immune infiltration compared to primary tumors. Further work to elucidate the specific cellular features of metastatic PDAC is needed to guide the development of future immunotherapy strategies. Here, we investigated the hypothesis that PDAC tumors harbor distinct immunologic and stromal features depending on their anatomical site. Multiplex immunohistochemistry (mIHC), spatial analysis, and single-cell mass cytometry (CyTOF) uncovered dominant immune and stromal cell populations in tumors derived from 27 primary and 26 liver metastases. Metastatic liver tumors from PDAC patients contained reduced T cell infiltration, fibroblast populations, and collagen accumulation than primary lesions, while CD68+ cells, often co-expressing CCR2, were more abundant. Spatial analyses revealed distinct immune cell communities in primary and metastatic PDAC, whereby CK19+ cells clustered differentially with α-SMA+, CD3+, and CD68+ cells, depending on the tumor site. When comparing tumor-associated regions, the proportion of peritumoral CK19- cells remained consistent, but their composition varied by disease site. CD8+ T cells were significantly less frequent in metastatic tumors, while both CD4+ and CD8+ T cells present in primary tumors expressed more transcription factors (TFs) associated with suppressive properties, including FoxP3 and RORγt. CyTOF revealed that T cells co-expressed multiple inhibitory checkpoint receptors, most notably LAG-3 and PD-1. This report reveals that primary and metastatic tumors from PDAC patients harbor vastly distinct immunologic and stromal features at the protein level.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"361 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1158/0008-5472.can-25-3189
Tu-Yung Chang,Yen-Wei Chien,Szu-Hua Chen,Annelise Sokolow,Yeh Wang,Brant G Wang,Tricia A Numan,M Herman Chui,Rebecca L Stone,Thomas R Pisanic,Nickolas Papadopoulos,Tian-Li Wang,Christopher Douville,Leslie Cope,Ie-Ming Shih
Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. Here, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinicopathological features in 166 ovarian precancerous lesions. Four pre-cancerous transcriptomic subtypes were identified: proliferative, immunoreactive, dormant, and mixed. These subtypes varied in their frequency of germline-BRCA1/2 mutations, aneuploidy, CCNE1/MYC amplification, proliferative activity, immune-regulatory gene expression, and histological features. Notably, the immunoreactive subtype upregulated immune-regulatory genes, exhibited chronic inflammation, and was enriched in cases with germline-BRCA1/2 mutations, deletions of chromosomes 17 (harboring TP53 and BRCA1) and 13 (harboring BRCA2), leading to a double "two-hit" involving TP53 and BRCA1/2. Tumor invasion was associated with the activation of interferon response pathways, epithelial-mesenchymal transition, and extracellular matrix remodeling. In summary, these results elucidate the earliest molecular landscape of ovarian precancerous lesions, serving as the foundation for future risk stratification to identify aggressive pre-cancerous lesions.
{"title":"Integrated Spatial Analysis Reveals the Molecular Landscape of Ovarian Precancerous Lesions.","authors":"Tu-Yung Chang,Yen-Wei Chien,Szu-Hua Chen,Annelise Sokolow,Yeh Wang,Brant G Wang,Tricia A Numan,M Herman Chui,Rebecca L Stone,Thomas R Pisanic,Nickolas Papadopoulos,Tian-Li Wang,Christopher Douville,Leslie Cope,Ie-Ming Shih","doi":"10.1158/0008-5472.can-25-3189","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-3189","url":null,"abstract":"Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. Here, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinicopathological features in 166 ovarian precancerous lesions. Four pre-cancerous transcriptomic subtypes were identified: proliferative, immunoreactive, dormant, and mixed. These subtypes varied in their frequency of germline-BRCA1/2 mutations, aneuploidy, CCNE1/MYC amplification, proliferative activity, immune-regulatory gene expression, and histological features. Notably, the immunoreactive subtype upregulated immune-regulatory genes, exhibited chronic inflammation, and was enriched in cases with germline-BRCA1/2 mutations, deletions of chromosomes 17 (harboring TP53 and BRCA1) and 13 (harboring BRCA2), leading to a double \"two-hit\" involving TP53 and BRCA1/2. Tumor invasion was associated with the activation of interferon response pathways, epithelial-mesenchymal transition, and extracellular matrix remodeling. In summary, these results elucidate the earliest molecular landscape of ovarian precancerous lesions, serving as the foundation for future risk stratification to identify aggressive pre-cancerous lesions.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"20 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1158/0008-5472.can-25-1402
Kimberly A Rivera-Caraballo,Tae Jin Lee,Arnoneel Sinha,Marco Orecchioni,Rafal Pacholczyk,Karina Vázquez-Arreguín,Shilpa Sharma,Kimya Jones,Kailash Vemuri,Upasana Sahu,Sara A Murphy,Bangxing Hong,Ravindra Kolhe,Ashok Sharma,Balveen Kaur
Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in recurrent high-grade glioma patients treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAMs), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the tumor microenvironment. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2/M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62 and autophagosome accumulation, and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and DAMPs, such as IL-1β, HMGB1, and extracellular ATP. Co-culturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and pro-inflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the anti-tumor therapeutic efficacy of OD-0J1.
{"title":"Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.","authors":"Kimberly A Rivera-Caraballo,Tae Jin Lee,Arnoneel Sinha,Marco Orecchioni,Rafal Pacholczyk,Karina Vázquez-Arreguín,Shilpa Sharma,Kimya Jones,Kailash Vemuri,Upasana Sahu,Sara A Murphy,Bangxing Hong,Ravindra Kolhe,Ashok Sharma,Balveen Kaur","doi":"10.1158/0008-5472.can-25-1402","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1402","url":null,"abstract":"Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in recurrent high-grade glioma patients treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAMs), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the tumor microenvironment. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2/M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62 and autophagosome accumulation, and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and DAMPs, such as IL-1β, HMGB1, and extracellular ATP. Co-culturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and pro-inflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the anti-tumor therapeutic efficacy of OD-0J1.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"23 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1158/0008-5472.can-25-1483
Kristiina Boettiger,Ildikó Kovács,Lilla Horvath,Büsra Ernhofer,Karin Schelch,Maria Dorothea Pozonec,Vivien Teglas,Clemens Aigner,Evelyn Megyesfalvi,Ferenc Rényi-Vámos,Krisztina Bogos,Christian Lang,Abigail J Deloria,Carl M Gay,Lauren A Byers,Julien Sage,Fred R Hirsch,Zsolt Megyesfalvi,Balazs Dome
Small cell lung cancer (SCLC) is an aggressive thoracic disease characterized by rapid proliferation and early metastatic spread. The survival outcomes for SCLC patients remain notoriously poor, underlining that only modest improvements have been achieved in clinical settings to date. However, insights gained from human tumors and preclinical models in recent years have shed light on the heterogeneous molecular profile of SCLC. Numerous research groups have, therefore, begun to stratify SCLC into subgroups based on differential transcription factor expression, the tumor immune microenvironment, and other criteria. Since SCLC subtypes show major differences in their molecular landscape and biological behavior, they may offer unique therapeutic vulnerabilities and serve as a framework for future personalized clinical trials. Here, we summarize impactful classification attempts from the last ten years, highlighting discrepancies and connections between the nomenclature of each study, and expound upon relevant factors of SCLC biology influencing subtype composition and plasticity. This review delves into the implications of subgrouping for understanding and treating SCLC as well as potential future directions for SCLC research.
{"title":"Small Cell Lung Cancer Classification: Unraveling Heterogeneity to Enable Personalized Treatments.","authors":"Kristiina Boettiger,Ildikó Kovács,Lilla Horvath,Büsra Ernhofer,Karin Schelch,Maria Dorothea Pozonec,Vivien Teglas,Clemens Aigner,Evelyn Megyesfalvi,Ferenc Rényi-Vámos,Krisztina Bogos,Christian Lang,Abigail J Deloria,Carl M Gay,Lauren A Byers,Julien Sage,Fred R Hirsch,Zsolt Megyesfalvi,Balazs Dome","doi":"10.1158/0008-5472.can-25-1483","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1483","url":null,"abstract":"Small cell lung cancer (SCLC) is an aggressive thoracic disease characterized by rapid proliferation and early metastatic spread. The survival outcomes for SCLC patients remain notoriously poor, underlining that only modest improvements have been achieved in clinical settings to date. However, insights gained from human tumors and preclinical models in recent years have shed light on the heterogeneous molecular profile of SCLC. Numerous research groups have, therefore, begun to stratify SCLC into subgroups based on differential transcription factor expression, the tumor immune microenvironment, and other criteria. Since SCLC subtypes show major differences in their molecular landscape and biological behavior, they may offer unique therapeutic vulnerabilities and serve as a framework for future personalized clinical trials. Here, we summarize impactful classification attempts from the last ten years, highlighting discrepancies and connections between the nomenclature of each study, and expound upon relevant factors of SCLC biology influencing subtype composition and plasticity. This review delves into the implications of subgrouping for understanding and treating SCLC as well as potential future directions for SCLC research.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1158/0008-5472.can-25-0453
Alexandra T Tankka,Yuhan Zhang,Jaclyn M Einstein,Catherine J Zhou,Vivian N Pham,Jack T Naritomi,Grady G Nguyen,Amaya N Mendez-Molina,Zhimin Hu,Orel Mizrahi,Mark Perelis,Joseph Sarsam,Frederick E Tan,Dan S Kaufman,Jing Yang,Corina E Antal,Gene W Yeo
RNA-binding proteins (RBPs) are important regulators of post-transcriptional gene expression. Understanding which and how RBPs promote cancer progression is crucial for cancers that lack effective targeted therapies, such as triple negative breast cancer (TNBC). Here, we employed both in vitro and in vivo pooled CRISPR/Cas9 screening to identify 50 RBP candidates essential for TNBC cell survival. Integrated eCLIP and RNA-sequencing analysis identified that poly(U)-binding splicing factor 60 (PUF60) drives exon inclusion within proliferation-associated transcripts that, when mis-spliced, induce cell cycle arrest and DNA damage. Furthermore, disrupting PUF60 interactions with 3' splice sites via a substitution in its RNA-binding domain caused widespread exon skipping, leading to downregulation of proliferation-associated mRNAs and inducing apoptosis in TNBC cells. Knockdown of PUF60 or disruption of PUF60-RNA interactions inhibited TNBC cell proliferation and shrunk tumor xenografts in multiple models. Together, these findings reveal the molecular mechanism by which PUF60 supports cancer progression.
{"title":"Integrative CRISPR Screening and RNA Analyses Discover an Essential Role for PUF60 Interactions with 3' Splice Sites in Cancer Progression.","authors":"Alexandra T Tankka,Yuhan Zhang,Jaclyn M Einstein,Catherine J Zhou,Vivian N Pham,Jack T Naritomi,Grady G Nguyen,Amaya N Mendez-Molina,Zhimin Hu,Orel Mizrahi,Mark Perelis,Joseph Sarsam,Frederick E Tan,Dan S Kaufman,Jing Yang,Corina E Antal,Gene W Yeo","doi":"10.1158/0008-5472.can-25-0453","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0453","url":null,"abstract":"RNA-binding proteins (RBPs) are important regulators of post-transcriptional gene expression. Understanding which and how RBPs promote cancer progression is crucial for cancers that lack effective targeted therapies, such as triple negative breast cancer (TNBC). Here, we employed both in vitro and in vivo pooled CRISPR/Cas9 screening to identify 50 RBP candidates essential for TNBC cell survival. Integrated eCLIP and RNA-sequencing analysis identified that poly(U)-binding splicing factor 60 (PUF60) drives exon inclusion within proliferation-associated transcripts that, when mis-spliced, induce cell cycle arrest and DNA damage. Furthermore, disrupting PUF60 interactions with 3' splice sites via a substitution in its RNA-binding domain caused widespread exon skipping, leading to downregulation of proliferation-associated mRNAs and inducing apoptosis in TNBC cells. Knockdown of PUF60 or disruption of PUF60-RNA interactions inhibited TNBC cell proliferation and shrunk tumor xenografts in multiple models. Together, these findings reveal the molecular mechanism by which PUF60 supports cancer progression.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777323","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}
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