Although neoadjuvant chemotherapy (NAC) has shown efficacy in reducing tumor burden in colorectal cancer (CRC), its impact on long-term patient outcomes remains limited. Here, we identify quiescent persister tumor cells (PTCs) as a critical determinant of therapeutic failure. Elevated PTC abundance correlates with poor long-term prognosis, even in patients exhibiting an initial response to treatment. Quiescent PTCs possess aggressive stem-like traits and orchestrate an immunosuppressive microenvironment characterized by CD96+CD8+ T cell infiltration in an orthotopic CRC mouse model. CD96 depletion diverts CD8+ T cells from an exhaustion trajectory and promotes memory-like phenotypes through enhanced mitochondrial function. Consistently, anti-CD96 therapy effectively eliminates PTCs in preclinical models. We also engineered epithelial cell adhesion molecule (EpCAM)-targeted human chimeric antigen receptor (CAR)-T cells deficient in CD96 expression, which robustly target PTCs and demonstrate remarkable therapeutic potential against CRC. Overall, our study uncovers CD96 as a previously unrecognized axis of vulnerability within the PTC-driven microenvironment, offering a promising avenue to enhance CRC therapeutic outcomes.
{"title":"Unleashing T cell surveillance for the eradication of quiescent persister tumor cells resistant to neoadjuvant chemotherapy","authors":"Haigang Geng, Hongye Wang, Chuanjie Zhang, Yangyang Zhou, Yiqing Zhong, Zhenhua Zhu, Zhaorong Wu, Tangansu Zhang, Nuo Xu, Zhongyi Dong, Haoyu Zhang, Qian Li, Yan Li, Xiangyu Tang, Xifu Cheng, Xiang Xia, Zizhen Zhang, Bo Zhai, Zhigang Zheng, Qing Li, Chunchao Zhu","doi":"10.1016/j.devcel.2026.02.020","DOIUrl":"https://doi.org/10.1016/j.devcel.2026.02.020","url":null,"abstract":"Although neoadjuvant chemotherapy (NAC) has shown efficacy in reducing tumor burden in colorectal cancer (CRC), its impact on long-term patient outcomes remains limited. Here, we identify quiescent persister tumor cells (PTCs) as a critical determinant of therapeutic failure. Elevated PTC abundance correlates with poor long-term prognosis, even in patients exhibiting an initial response to treatment. Quiescent PTCs possess aggressive stem-like traits and orchestrate an immunosuppressive microenvironment characterized by CD96<sup>+</sup>CD8<sup>+</sup> T cell infiltration in an orthotopic CRC mouse model. CD96 depletion diverts CD8<sup>+</sup> T cells from an exhaustion trajectory and promotes memory-like phenotypes through enhanced mitochondrial function. Consistently, anti-CD96 therapy effectively eliminates PTCs in preclinical models. We also engineered epithelial cell adhesion molecule (EpCAM)-targeted human chimeric antigen receptor (CAR)-T cells deficient in CD96 expression, which robustly target PTCs and demonstrate remarkable therapeutic potential against CRC. Overall, our study uncovers CD96 as a previously unrecognized axis of vulnerability within the PTC-driven microenvironment, offering a promising avenue to enhance CRC therapeutic outcomes.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"22 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507365","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 : 2026-03-24DOI: 10.1016/j.devcel.2026.03.009
Zhen Zhang, Ben Jin, Chenyu You, Ya Li, Li Lin, Jianlong Sun
{"title":"Hematopoietic stem cells activate a latent differentiation pathway to facilitate recovery after 5-fluorouracil-induced myeloablation","authors":"Zhen Zhang, Ben Jin, Chenyu You, Ya Li, Li Lin, Jianlong Sun","doi":"10.1016/j.devcel.2026.03.009","DOIUrl":"https://doi.org/10.1016/j.devcel.2026.03.009","url":null,"abstract":"","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"14 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501745","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 : 2026-03-23DOI: 10.1016/j.devcel.2026.02.017
Stefan R. Torborg, Jung Yun Kim, Anupriya Singhal, Olivera Grbovic-Huezo, Matilda Holm, Katherine Wu, Xuexiang Han, Yu-Jui Ho, Caj Haglund, Michael J. Mitchell, Scott W. Lowe, Lukas E. Dow, Kenneth L. Pitter, Francisco J. Sanchez-Rivera, Andre Levchenko, Tuomas Tammela
{"title":"Disruption of WNT/Notch signaling in pancreatic cancer reveals tumors depend on the intricate equilibrium of malignant cell states","authors":"Stefan R. Torborg, Jung Yun Kim, Anupriya Singhal, Olivera Grbovic-Huezo, Matilda Holm, Katherine Wu, Xuexiang Han, Yu-Jui Ho, Caj Haglund, Michael J. Mitchell, Scott W. Lowe, Lukas E. Dow, Kenneth L. Pitter, Francisco J. Sanchez-Rivera, Andre Levchenko, Tuomas Tammela","doi":"10.1016/j.devcel.2026.02.017","DOIUrl":"https://doi.org/10.1016/j.devcel.2026.02.017","url":null,"abstract":"","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"219 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501750","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 : 2026-03-23DOI: 10.1016/j.devcel.2026.02.018
Miguel F. Tenreiro, Alysson R. Muotri
{"title":"Reconstructing human corticogenesis: Insights from cerebral organoids into neurodevelopment and disease modeling","authors":"Miguel F. Tenreiro, Alysson R. Muotri","doi":"10.1016/j.devcel.2026.02.018","DOIUrl":"https://doi.org/10.1016/j.devcel.2026.02.018","url":null,"abstract":"","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"57 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501749","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 : 2026-03-17DOI: 10.1016/j.devcel.2026.02.016
Konstantinos Stamatiou, Florentin Huguet, Marta Budzinska, Jose I de Las Heras, Denise Ragusa, Ines J deCastro, Christos Spanos, Juri Rappsilberg, Paola Vagnarelli
Mitotic exit is an important part of the cell cycle, requiring the coordination of many chromatin and cytoskeleton remodeling events to successfully complete cell division and maintain cell identity. Protein dephosphorylation is a key step in directing mitotic exit, and protein phosphatase 1 (PP1) is essential to this process; however, the specific contribution of its numerous targeting subunits is still unknown. Here, we have investigated the function of three chromatin-associated PP1-targeting subunits in mitosis exit: Repo-Man, Ki-67, and protein phosphatase 1 nuclear targeting subunit (PNUTS). We generated endogenously tagged, auxin-degradable alleles for each subunit in the human cell line HCT116 and used a multi-omic approach to address their specific contributions toward transcription resumption, chromatin accessibility, and protein dephosphorylation at the transition from mitosis to G1. This approach identified their distinct role in mitotic exit, provided datasets for the cell-cycle community, and highlighted functions for Ki-67 and Repo-Man in genome stability and organization.
{"title":"Multi-omic analyses reveal a differential contribution of chromatin-associated PP1 holoenzymes to mitotic exit and G1 re-establishment.","authors":"Konstantinos Stamatiou, Florentin Huguet, Marta Budzinska, Jose I de Las Heras, Denise Ragusa, Ines J deCastro, Christos Spanos, Juri Rappsilberg, Paola Vagnarelli","doi":"10.1016/j.devcel.2026.02.016","DOIUrl":"https://doi.org/10.1016/j.devcel.2026.02.016","url":null,"abstract":"<p><p>Mitotic exit is an important part of the cell cycle, requiring the coordination of many chromatin and cytoskeleton remodeling events to successfully complete cell division and maintain cell identity. Protein dephosphorylation is a key step in directing mitotic exit, and protein phosphatase 1 (PP1) is essential to this process; however, the specific contribution of its numerous targeting subunits is still unknown. Here, we have investigated the function of three chromatin-associated PP1-targeting subunits in mitosis exit: Repo-Man, Ki-67, and protein phosphatase 1 nuclear targeting subunit (PNUTS). We generated endogenously tagged, auxin-degradable alleles for each subunit in the human cell line HCT116 and used a multi-omic approach to address their specific contributions toward transcription resumption, chromatin accessibility, and protein dephosphorylation at the transition from mitosis to G1. This approach identified their distinct role in mitotic exit, provided datasets for the cell-cycle community, and highlighted functions for Ki-67 and Repo-Man in genome stability and organization.</p>","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480052","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}
Unexplored biological matter—including uncharacterized genetic elements, molecular entities, and microbial components—remains poorly understood. Here, we use integrated multi-omics approaches to identify and characterize previously unrecognized protein products encoded by circular RNAs (circRNAs) in human tissue specimens and to delineate their roles in the progression of lung adenocarcinoma (LUAD). The transcription of precursor mRNA by RNA polymerase Ⅱ subunit A (RPB1) is crucial for the biogenesis of these potential circRNA-encoded proteins. Functional and translational analyses link their expression to distinct pathological stages of LUAD in patients. The protein RIPK1-98, encoded by circRIPK1, was identified as functionally distinct from its parental gene product, receptor-interacting serine/threonine kinase 1 (RIPK1). RIPK1-98 modulates cyclin-dependent kinase 2 (CDK2)-dependent cell-cycle regulation, thereby facilitating tumor proliferation in cellular and animal models. Together, these findings suggest that RIPK1-98 serves as a biomarker for cell-cycle progression in LUAD and highlight its potential as a therapeutic target to counteract resistance to first-line treatments, such as osimertinib.
{"title":"CircRNA-encoded RIPK1-98 protein drives lung adenocarcinoma progression","authors":"Qi Sun, Runqiu Chi, Xiao Zhang, Tianxiang Chen, Xin Xu, Lifang Ma, Xiaoting Tian, Yayou Miao, Yongchun Yu, Rui Kang, Guido Kroemer, Yi Shi, Daolin Tang, Jiayi Wang","doi":"10.1016/j.devcel.2026.02.014","DOIUrl":"https://doi.org/10.1016/j.devcel.2026.02.014","url":null,"abstract":"Unexplored biological matter—including uncharacterized genetic elements, molecular entities, and microbial components—remains poorly understood. Here, we use integrated multi-omics approaches to identify and characterize previously unrecognized protein products encoded by circular RNAs (circRNAs) in human tissue specimens and to delineate their roles in the progression of lung adenocarcinoma (LUAD). The transcription of precursor mRNA by RNA polymerase Ⅱ subunit A (RPB1) is crucial for the biogenesis of these potential circRNA-encoded proteins. Functional and translational analyses link their expression to distinct pathological stages of LUAD in patients. The protein RIPK1-98, encoded by <em>circRIPK1</em>, was identified as functionally distinct from its parental gene product, <em>receptor-interacting serine/threonine kinase 1</em> (<em>RIPK1</em>). RIPK1-98 modulates cyclin-dependent kinase 2 (CDK2)-dependent cell-cycle regulation, thereby facilitating tumor proliferation in cellular and animal models. Together, these findings suggest that RIPK1-98 serves as a biomarker for cell-cycle progression in LUAD and highlight its potential as a therapeutic target to counteract resistance to first-line treatments, such as osimertinib.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"9 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447601","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 : 2026-03-12DOI: 10.1016/j.devcel.2026.02.013
Alec D’Alessandro, Kwabena Badu-Nkansah, Sophia Link, Daniel Hlavaty, Glenn Bjerke, Christopher V. Nicchitta, Rui Yi, Terry Lechler
Subcellular compartmentalization allows cells to spatially control molecular functions. We show that in mouse and human epidermal cells, translational machinery is enriched at the cell cortex, where a large subset of mRNAs is also localized, defining a previously unrecognized axis of mRNA organization. The desmosomal protein desmoplakin is required for the cortical recruitment of both ribosomes and mRNAs via distinct mechanisms. Surprisingly, many cortex-localized transcripts are not actively translated but instead are translationally repressed. This spatially restricted regulation involves the RNA-induced silencing complex (RISC), which is also enriched at the cortex in a desmoplakin-dependent manner. Under homeostatic conditions, cortical RISC associates with mRNAs encoding cell adhesion and cytoskeletal proteins. Following wounding, these RISC-associated transcripts become translationally activated. Together, our findings reveal a dynamic, desmosome-dependent cortical compartmentalization of translation that responds to epithelial barrier disruption.
{"title":"Desmosomes compartmentalize mRNA and translation in the skin","authors":"Alec D’Alessandro, Kwabena Badu-Nkansah, Sophia Link, Daniel Hlavaty, Glenn Bjerke, Christopher V. Nicchitta, Rui Yi, Terry Lechler","doi":"10.1016/j.devcel.2026.02.013","DOIUrl":"https://doi.org/10.1016/j.devcel.2026.02.013","url":null,"abstract":"Subcellular compartmentalization allows cells to spatially control molecular functions. We show that in mouse and human epidermal cells, translational machinery is enriched at the cell cortex, where a large subset of mRNAs is also localized, defining a previously unrecognized axis of mRNA organization. The desmosomal protein desmoplakin is required for the cortical recruitment of both ribosomes and mRNAs via distinct mechanisms. Surprisingly, many cortex-localized transcripts are not actively translated but instead are translationally repressed. This spatially restricted regulation involves the RNA-induced silencing complex (RISC), which is also enriched at the cortex in a desmoplakin-dependent manner. Under homeostatic conditions, cortical RISC associates with mRNAs encoding cell adhesion and cytoskeletal proteins. Following wounding, these RISC-associated transcripts become translationally activated. Together, our findings reveal a dynamic, desmosome-dependent cortical compartmentalization of translation that responds to epithelial barrier disruption.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"16 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447602","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 : 2026-03-11DOI: 10.1016/j.devcel.2026.02.015
Iosifina P. Foskolou
In this issue of Developmental Cell, Wu et al. report that the active form of vitamin B6, pyridoxal phosphate (PLP), enhances CD8+ T cell-dependent tumor clearance. Mechanistically, PLP maintains CD8+ T cells in a stemness-like state by inhibiting the nuclear translocation of BACH2. Here, we discuss these findings and their implications for cancer immunotherapy.
{"title":"Vitamin B6 modulates CD8+ T cell antitumor responses","authors":"Iosifina P. Foskolou","doi":"10.1016/j.devcel.2026.02.015","DOIUrl":"https://doi.org/10.1016/j.devcel.2026.02.015","url":null,"abstract":"In this issue of <em>Developmental Cell</em>, Wu et al. report that the active form of vitamin B6, pyridoxal phosphate (PLP), enhances CD8<sup>+</sup> T cell-dependent tumor clearance. Mechanistically, PLP maintains CD8<sup>+</sup> T cells in a stemness-like state by inhibiting the nuclear translocation of BACH2. Here, we discuss these findings and their implications for cancer immunotherapy.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"74 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393444","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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