Pub Date : 2025-09-08DOI: 10.1016/j.devcel.2025.06.032
G. Kenneth Gray, Eric G. Carlson, Tatyana Lev, Bailey Marshall, Austin D. Reed, Alex P. Sánchez-Covarrubias, Alecia-Jane Twigger, Aleix Puig-Barbe, Aatish Thennavan, Ayodele Omotoso, Lyndsay M. Murrow, Deeptiman Chatterjee, Siyuan He, Sara Pensa, Brian Aevermann, Norbert K. Tavares, Natalie Chen, Jason A. Hilton, Kerrigan Blake, Yunlong Liu, Walid T. Khaled
Single-cell studies on breast tissue have contributed to a change in our understanding of breast epithelial diversity that has, in turn, precipitated a lack of consensus on breast cell types. The confusion surrounding this issue highlights a possible challenge for advancing breast atlas efforts. In this perspective, we present our consensus on the identities, properties, and naming conventions for breast epithelial cell types and propose goals for future atlas endeavors. Our proposals and their underlying thought processes aim to catalyze the adoption of a shared model for this tissue and to serve as guidance for other investigators facing similar challenges.
{"title":"Defining breast epithelial cell types in the single-cell era","authors":"G. Kenneth Gray, Eric G. Carlson, Tatyana Lev, Bailey Marshall, Austin D. Reed, Alex P. Sánchez-Covarrubias, Alecia-Jane Twigger, Aleix Puig-Barbe, Aatish Thennavan, Ayodele Omotoso, Lyndsay M. Murrow, Deeptiman Chatterjee, Siyuan He, Sara Pensa, Brian Aevermann, Norbert K. Tavares, Natalie Chen, Jason A. Hilton, Kerrigan Blake, Yunlong Liu, Walid T. Khaled","doi":"10.1016/j.devcel.2025.06.032","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.032","url":null,"abstract":"Single-cell studies on breast tissue have contributed to a change in our understanding of breast epithelial diversity that has, in turn, precipitated a lack of consensus on breast cell types. The confusion surrounding this issue highlights a possible challenge for advancing breast atlas efforts. In this perspective, we present our consensus on the identities, properties, and naming conventions for breast epithelial cell types and propose goals for future atlas endeavors. Our proposals and their underlying thought processes aim to catalyze the adoption of a shared model for this tissue and to serve as guidance for other investigators facing similar challenges.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"27 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1016/j.devcel.2025.06.010
Lisa B. Earnest-Noble, Bradley J. Goldstein
Understanding tumor cell plasticity, a potential mechanism driving therapeutic resistance in many cancers, represents a key oncologic challenge. In this issue of Developmental Cell, Xu et al. leverage neuroblastoma as a tractable model for exploring mechanisms of tumor plasticity and provide key insights into drivers of tumor cell states.
{"title":"A bridge too far: Identification of bridge cell states as drivers of plasticity in neuroblastoma","authors":"Lisa B. Earnest-Noble, Bradley J. Goldstein","doi":"10.1016/j.devcel.2025.06.010","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.010","url":null,"abstract":"Understanding tumor cell plasticity, a potential mechanism driving therapeutic resistance in many cancers, represents a key oncologic challenge. In this issue of <em>Developmental Cell</em>, Xu et al. leverage neuroblastoma as a tractable model for exploring mechanisms of tumor plasticity and provide key insights into drivers of tumor cell states.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"132 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-05DOI: 10.1016/j.devcel.2025.08.014
Xiangyi Ke, Benjamin van Soldt, Lukas Vlahos, Yizhuo Zhou, Jun Qian, Pasquale Laise, Joel George, Claudia Capdevila, Ian Glass, Kelley Yan, Andrea Califano, Wellington V. Cardoso
(Developmental Cell 60, 819–836.e1–e7; March 24, 2025)
（《发育细胞》60期，819-836.e1-e7； 2025年3月24日）
{"title":"Morphogenesis and regeneration share a conserved core transition cell state program that controls lung epithelial cell fate","authors":"Xiangyi Ke, Benjamin van Soldt, Lukas Vlahos, Yizhuo Zhou, Jun Qian, Pasquale Laise, Joel George, Claudia Capdevila, Ian Glass, Kelley Yan, Andrea Califano, Wellington V. Cardoso","doi":"10.1016/j.devcel.2025.08.014","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.08.014","url":null,"abstract":"(Developmental Cell <em>60</em>, 819–836.e1–e7; March 24, 2025)","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"16 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-02DOI: 10.1016/j.devcel.2025.08.005
Yumiko K. Kawamura, Evgeniy A. Ozonov, Panagiotis Papasaikas, Takashi Kondo, Nhuong V. Nguyen, Michael B. Stadler, Sebastien A. Smallwood, Haruhiko Koseki, Antoine H.F.M. Peters
Except for regulatory CpG-island sequences, genomes of most mammalian cells are widely DNA-methylated. In oocytes, though, DNA methylation (DNAme) is largely confined to transcribed regions. The mechanisms restricting de novo DNAme in oocytes and their relevance thereof for zygotic genome activation and embryonic development are largely unknown. Here we show that KDM2A and KDM2B, two histone demethylases, prevent genome-wide accumulation of histone H3 lysine 36 di-methylation, thereby impeding DNMT3A-catalyzed DNAme. We demonstrate that aberrant DNAme at CpG islands inherited from Kdm2a/Kdm2b double-mutant oocytes represses gene transcription in two-cell embryos. Aberrant maternal DNAme impairs pre-implantation embryonic development, which is suppressed by Dnmt3a deficiency during oogenesis. Hence, KDM2A/KDM2B are essential for confining the oocyte methylome, thereby conferring competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient for erasing aberrant DNAme from maternal chromatin, and that early development is susceptible to gene dosage haplo-insufficiency effects.
{"title":"Preventing CpG hypermethylation in oocytes safeguards mouse development","authors":"Yumiko K. Kawamura, Evgeniy A. Ozonov, Panagiotis Papasaikas, Takashi Kondo, Nhuong V. Nguyen, Michael B. Stadler, Sebastien A. Smallwood, Haruhiko Koseki, Antoine H.F.M. Peters","doi":"10.1016/j.devcel.2025.08.005","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.08.005","url":null,"abstract":"Except for regulatory CpG-island sequences, genomes of most mammalian cells are widely DNA-methylated. In oocytes, though, DNA methylation (DNAme) is largely confined to transcribed regions. The mechanisms restricting <em>de novo</em> DNAme in oocytes and their relevance thereof for zygotic genome activation and embryonic development are largely unknown. Here we show that KDM2A and KDM2B, two histone demethylases, prevent genome-wide accumulation of histone H3 lysine 36 di-methylation, thereby impeding DNMT3A-catalyzed DNAme. We demonstrate that aberrant DNAme at CpG islands inherited from <em>Kdm2a/Kdm2b</em> double-mutant oocytes represses gene transcription in two-cell embryos. Aberrant maternal DNAme impairs pre-implantation embryonic development, which is suppressed by <em>Dnmt3a</em> deficiency during oogenesis. Hence, KDM2A/KDM2B are essential for confining the oocyte methylome, thereby conferring competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient for erasing aberrant DNAme from maternal chromatin, and that early development is susceptible to gene dosage haplo-insufficiency effects.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"28 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-28DOI: 10.1016/j.devcel.2025.08.004
Victoria Jorgensen, Min Bao, Sergi Junyent, Christoph M. Häfelfinger, Laura Amaya, Zhaodi Liao, Brian A. Williams, Dong-Yuan Chen, Amanda Wu, Matt Thomson, Magdalena Zernicka-Goetz
Blastoids are stem cell-derived structures that mimic natural blastocysts by incorporating all three lineages: trophectoderm, epiblast, and primitive endoderm. However, current methods often yield incomplete structures that fail to cavitate or to form a proper primitive endoderm. To overcome these limitations, we develop a modular approach by aggregating three murine stem cell types: embryonic stem cells (ESCs), ESCs with inducible GATA4 expression (iG4-ESCs), and trophoblast stem cells (TSCs). This method yields cavitated blastocyst-like structures—termed iG4-blastoids—with approximately 80% efficiency. Single-cell RNA sequencing confirms their close resemblance to mature mouse blastocysts. Notably, culturing iG4-blastoids without FGF4 enhances specification of the invasive mural trophectoderm, and approximately 12% of structures undergo post-implantation-like morphogenesis in vitro. Using this model, we show that caffeine, alcohol, nicotine, and amino acid variations affect iG4-blastoids and natural embryos similarly, underscoring their utility as a robust model for investigating the impact of diverse environmental factors on embryogenesis.
{"title":"Efficient stem cell-derived mouse embryo models for environmental studies","authors":"Victoria Jorgensen, Min Bao, Sergi Junyent, Christoph M. Häfelfinger, Laura Amaya, Zhaodi Liao, Brian A. Williams, Dong-Yuan Chen, Amanda Wu, Matt Thomson, Magdalena Zernicka-Goetz","doi":"10.1016/j.devcel.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.08.004","url":null,"abstract":"Blastoids are stem cell-derived structures that mimic natural blastocysts by incorporating all three lineages: trophectoderm, epiblast, and primitive endoderm. However, current methods often yield incomplete structures that fail to cavitate or to form a proper primitive endoderm. To overcome these limitations, we develop a modular approach by aggregating three murine stem cell types: embryonic stem cells (ESCs), ESCs with inducible GATA4 expression (iG4-ESCs), and trophoblast stem cells (TSCs). This method yields cavitated blastocyst-like structures—termed iG4-blastoids—with approximately 80% efficiency. Single-cell RNA sequencing confirms their close resemblance to mature mouse blastocysts. Notably, culturing iG4-blastoids without FGF4 enhances specification of the invasive mural trophectoderm, and approximately 12% of structures undergo post-implantation-like morphogenesis <em>in vitro</em>. Using this model, we show that caffeine, alcohol, nicotine, and amino acid variations affect iG4-blastoids and natural embryos similarly, underscoring their utility as a robust model for investigating the impact of diverse environmental factors on embryogenesis.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"52 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144911213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-27DOI: 10.1016/j.devcel.2025.08.007
Xin Tian, Jian Xu
Uncovering plant cell types and regulatory genes across species has long been a challenge. Writing in Cell, Xue et al. present single-cell atlases for six vascular plants and identify conserved “cell-type foundational genes.” These enable cross-species annotation, speeding up discoveries in plant and evolutionary biology and ultimately supporting crop improvement.
{"title":"Decoding plant cell types across species: A blueprint for gene discovery","authors":"Xin Tian, Jian Xu","doi":"10.1016/j.devcel.2025.08.007","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.08.007","url":null,"abstract":"Uncovering plant cell types and regulatory genes across species has long been a challenge. Writing in <em>Cell</em>, Xue et al. present single-cell atlases for six vascular plants and identify conserved “cell-type foundational genes.” These enable cross-species annotation, speeding up discoveries in plant and evolutionary biology and ultimately supporting crop improvement.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"106 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumor-antigen-specific CD8+ T cells (CTLs) are the main effector immunocytes in anti-tumor immunity, but their systemic deployment against cancer metastasis remains uncharacterized. Here, we found that the abundance of tumor-specific CD103+CD8+ T cells in the tumor-draining lymph nodes (TDLNs) was associated with improved lung-metastasis-free survival in breast cancer patients. In mouse cancer models, CD103+CD8+ T cells were primed in TDLNs and recruited to the lungs via C-C motif chemokine ligand 5/receptor 9 (CCL25/CCR9) signaling to inhibit metastasis through antigen-specific immunity. Furthermore, extracellular vesicles (EVs) from early- and late-stage tumors differentially polarized alveolar macrophages to release CCL25 and IDO1, respectively, and the latter impaired pulmonary CD103+CD8+ T cell deployment, facilitating lung metastasis. Depleting IDO1 effectively rescued CD103+CD8+ T cell-mediated protection against lung metastasis. These findings exemplified long-range deployment of adaptive immunity to protect distant organs from metastasis, highlighting the therapeutic potential of reconstituting effector immune cell deployment (EICD) for cancer treatment.
{"title":"Long-range deployment of tumor-antigen-specific cytotoxic T lymphocytes inhibits lung metastasis of breast cancer","authors":"Yue Xing, Yan Zhou, Ruxin Wang, Jianing Chen, Linbin Yang, Xiangyu Meng, Jiawen Wang, Qian Ouyang, Jinghua Zhao, Fei Chen, Phei Er Saw, Jia Fan, Jian-Dong Huang, Wei Wu, Qiang Liu, Erwei Song, Di Huang","doi":"10.1016/j.devcel.2025.08.003","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.08.003","url":null,"abstract":"Tumor-antigen-specific CD8<sup>+</sup> T cells (CTLs) are the main effector immunocytes in anti-tumor immunity, but their systemic deployment against cancer metastasis remains uncharacterized. Here, we found that the abundance of tumor-specific CD103<sup>+</sup>CD8<sup>+</sup> T cells in the tumor-draining lymph nodes (TDLNs) was associated with improved lung-metastasis-free survival in breast cancer patients. In mouse cancer models, CD103<sup>+</sup>CD8<sup>+</sup> T cells were primed in TDLNs and recruited to the lungs via C-C motif chemokine ligand 5/receptor 9 (CCL25/CCR9) signaling to inhibit metastasis through antigen-specific immunity. Furthermore, extracellular vesicles (EVs) from early- and late-stage tumors differentially polarized alveolar macrophages to release CCL25 and IDO1, respectively, and the latter impaired pulmonary CD103<sup>+</sup>CD8<sup>+</sup> T cell deployment, facilitating lung metastasis. Depleting IDO1 effectively rescued CD103<sup>+</sup>CD8<sup>+</sup> T cell-mediated protection against lung metastasis. These findings exemplified long-range deployment of adaptive immunity to protect distant organs from metastasis, highlighting the therapeutic potential of reconstituting effector immune cell deployment (EICD) for cancer treatment.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"102 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-27DOI: 10.1016/j.devcel.2025.08.001
Daniel Medina-Cano, Mohammed T. Islam, Veronika Petrova, Sanjana Dixit, Zerina Balic, Marty G. Yang, Matthias Stadtfeld, Emily S. Wong, Thomas Vierbuchen
Natural selection has shaped the gene regulatory networks that orchestrate cortical development, leading to structural and functional variation across mammals, but the molecular and cellular mechanisms underpinning these changes have only begun to be characterized. Here, we develop a reproducible protocol for cerebral cortex organoid generation from mouse epiblast stem cells (EpiSCs), which recapitulates the timing and cellular differentiation programs of the embryonic cortex. We generated cortical organoids from F1 hybrid EpiSCs derived from crosses between laboratory mice (C57BL/6J) and four wild-derived inbred strains spanning ∼1 M years of evolutionary divergence to comprehensively map cis-acting transcriptional regulatory variation across developing cortical cell types, using single-cell RNA sequencing (scRNA-seq). We identify hundreds of genes that exhibit dynamic allelic imbalances, providing the first insight into the developmental mechanisms underpinning changes in cortical structure and function between subspecies. These experimental methods and cellular resources represent a powerful platform for investigating gene regulation in the developing cerebral cortex.
{"title":"A mouse organoid platform for modeling cerebral cortex development and cis-regulatory evolution in vitro","authors":"Daniel Medina-Cano, Mohammed T. Islam, Veronika Petrova, Sanjana Dixit, Zerina Balic, Marty G. Yang, Matthias Stadtfeld, Emily S. Wong, Thomas Vierbuchen","doi":"10.1016/j.devcel.2025.08.001","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.08.001","url":null,"abstract":"Natural selection has shaped the gene regulatory networks that orchestrate cortical development, leading to structural and functional variation across mammals, but the molecular and cellular mechanisms underpinning these changes have only begun to be characterized. Here, we develop a reproducible protocol for cerebral cortex organoid generation from mouse epiblast stem cells (EpiSCs), which recapitulates the timing and cellular differentiation programs of the embryonic cortex. We generated cortical organoids from F1 hybrid EpiSCs derived from crosses between laboratory mice (C57BL/6J) and four wild-derived inbred strains spanning ∼1 M years of evolutionary divergence to comprehensively map <em>cis</em>-acting transcriptional regulatory variation across developing cortical cell types, using single-cell RNA sequencing (scRNA-seq). We identify hundreds of genes that exhibit dynamic allelic imbalances, providing the first insight into the developmental mechanisms underpinning changes in cortical structure and function between subspecies. These experimental methods and cellular resources represent a powerful platform for investigating gene regulation in the developing cerebral cortex.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"28 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-26DOI: 10.1016/j.devcel.2025.07.023
Deli Hong, Ying Lyu, Richa Nayak, Justin S. Becker, Matthew A. Booker, Keita Masuzawa, Zoe Devos, Tianchu Wang, Shin Saito, Qi Liu, Yixiang Li, Zhaorong Li, Eric H. Knelson, Tran Thai, Leslie Duplaquet, Yasmin N. Laimon, Gabriel Roberti De Oliveira, Sabina Signoretti, John G. Doench, David A. Barbie, Matthew G. Oser
Small cell lung cancer (SCLC) is a highly aggressive malignancy that lacks effective targeted therapies, in part due to frequent loss-of-function mutations in tumor suppressors and the absence of recurrent oncogenic drivers. Approximately 15% of SCLCs harbor inactivating mutations in NOTCH1 or NOTCH2, and most neuroendocrine-high SCLCs exhibit low NOTCH activity. Using CRISPR-Cas9 screening in primary cell lines derived from NOTCH1/2-isogenic SCLC genetically engineered mouse models, we identified TRIM28 as a synthetic lethal dependency in NOTCH2-inactivated SCLCs. Loss of TRIM28 in this context robustly induced expression of endogenous retroviruses (ERVs), activated viral sensing pathways, and triggered a type I interferon response. Mechanistically, NOTCH2 inactivation increased reliance on TRIM28-mediated ERV silencing, creating a hyperdependence on TRIM28 via the STING-MAVS-TBK1 axis. Notably, TRIM28 was essential for tumor growth only in the setting of NOTCH2 loss. These findings identify TRIM28 as a potential therapeutic target in NOTCH2-deficient or low-NOTCH2-expressing SCLC.
{"title":"Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer","authors":"Deli Hong, Ying Lyu, Richa Nayak, Justin S. Becker, Matthew A. Booker, Keita Masuzawa, Zoe Devos, Tianchu Wang, Shin Saito, Qi Liu, Yixiang Li, Zhaorong Li, Eric H. Knelson, Tran Thai, Leslie Duplaquet, Yasmin N. Laimon, Gabriel Roberti De Oliveira, Sabina Signoretti, John G. Doench, David A. Barbie, Matthew G. Oser","doi":"10.1016/j.devcel.2025.07.023","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.07.023","url":null,"abstract":"Small cell lung cancer (SCLC) is a highly aggressive malignancy that lacks effective targeted therapies, in part due to frequent loss-of-function mutations in tumor suppressors and the absence of recurrent oncogenic drivers. Approximately 15% of SCLCs harbor inactivating mutations in <em>NOTCH1</em> or <em>NOTCH2</em>, and most neuroendocrine-high SCLCs exhibit low NOTCH activity. Using CRISPR-Cas9 screening in primary cell lines derived from <em>NOTCH1/2</em>-isogenic SCLC genetically engineered mouse models, we identified TRIM28 as a synthetic lethal dependency in <em>NOTCH2</em>-inactivated SCLCs. Loss of TRIM28 in this context robustly induced expression of endogenous retroviruses (ERVs), activated viral sensing pathways, and triggered a type I interferon response. Mechanistically, <em>NOTCH2</em> inactivation increased reliance on TRIM28-mediated ERV silencing, creating a hyperdependence on TRIM28 via the STING-MAVS-TBK1 axis. Notably, TRIM28 was essential for tumor growth only in the setting of <em>NOTCH2</em> loss. These findings identify TRIM28 as a potential therapeutic target in <em>NOTCH2</em>-deficient or low-<em>NOTCH2</em>-expressing SCLC.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"13 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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