{"title":"STING reprogramming by estrogen promotes neutrophil extracellular trap formation and sex-biased resistance to ADC therapy.","authors":"Jingrui Yan, Tianxing Zhou, Shangheng Shi, Guohua Mao, Jingbo Xu, Yu Zhang, Yaqi Zhang, Huizhi Sun, Yifei Wang, Xiuchao Wang, Chongbiao Huang, Rui Liu, Deqing Hu, Shengyu Yang, Jun Yu, Yukuan Feng, Yongjie Xie, Bin Wang, Jihui Hao","doi":"10.1016/j.cell.2026.09.031","DOIUrl":"10.1016/j.cell.2026.09.031","url":null,"abstract":"<p><p>Sex differences in cancer therapy response remain poorly understood. Using a \"phase II-like preclinical trial\" across 55 CLDN18.2<sup>+</sup> pancreatic cancer patient-derived xenografts, we identify marked female-biased resistance to CLDN18.2-targeted antibody-drug conjugate (ADC) therapy despite equivalent antigen expression. Mechanistically, estrogen signals through GPER1 to upregulate TRAF6, redirecting tumor-intrinsic STING signaling from IRF3-mediated interferon production toward nuclear factor κB (NF-κB) activation. This drives CXCL1 secretion, neutrophil recruitment, and neutrophil extracellular trap (NET) formation. NETs form a charged extracellular network that restricts antibody access to tumor-cell-surface antigens-a mechanism we term functional antigen shielding-reducing ADC cytotoxicity independently of antigen expression. The NET burden also correlated with poorer responses to trastuzumab, cetuximab, and enfortumab vedotin across three clinical cohorts. Pharmacologic NET disruption with sivelestat restored ADC efficacy in female mice. These findings reveal an estrogen-driven resistance mechanism with broad implications for antibody-based cancer therapy.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"6752-6770.e21"},"PeriodicalIF":45.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104538","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}
CellPub Date : 2026-10-15DOI: 10.1016/j.cell.2026.08.044
Fei Chen,Evan Z. Macosko
{"title":"Cellular scaling laws in the mammalian brain","authors":"Fei Chen,Evan Z. Macosko","doi":"10.1016/j.cell.2026.08.044","DOIUrl":"https://doi.org/10.1016/j.cell.2026.08.044","url":null,"abstract":"Recent whole-brain cell atlases have uncovered a consistent cytoarchitectural feature: the greatest diversity of discrete neuronal cell types resides not in the regions with the most neurons (e.g., the cortex and cerebellum) but rather in deep subcortical structures like the hypothalamus and brain stem. We propose that this discrepancy reflects a fundamental algorithmic division in the vertebrate brain between a “learning subsystem” and a “steering subsystem.” The learning subsystem (cortex, striatum, and cerebellum) scales via the replication of repetitive modules to maximize computational capacity, analogous to scaling up parameters in machine learning models. By contrast, the steering subsystem (hypothalamus, pallidum, and brainstem) scales via diversification of bespoke cell types to encode innate drives and reflexes, functioning as a high-dimensional biological “reward function.” This framework explains the divergence in how evolution has influenced these subsystems and offers a unified lens for understanding brain architecture and the etiology of brain disease; furthermore, it may inform model designs for artificial intelligence.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"53 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173090","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}
{"title":"Cellular self-organization orchestrates ferroptosis propagation","authors":"Jen-Hao Cheng,Hannah K.C. Co,Hao-Kuen Lin,Chia-Chou Wu,Sheng-hong Chen","doi":"10.1016/j.cell.2026.09.039","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.039","url":null,"abstract":"Self-organization generates cellular patterns that guide morphogenesis, but how it regulates collective cell fate remains underexplored. We show that cellular self-organization constrains the propagation of ferroptosis, an iron-dependent form of oxidative cell death that can otherwise spread as unbounded trigger waves. The spatial patterning of cell density and alignment encodes transcriptional programs, priming cells toward ferroptosis-sensitive or -resistant fates. Low-density, misaligned regions with elevated YAP/TEAD1 activity are sensitive, whereas high-density, aligned regions with increased NRF2 expression form propagation-resistant boundaries. Cell elongation establishes a polarized distribution of oxidizable lipids, creating peroxidation hotspots at the cell poles that promote propagation along cell alignment. In silico and pharmacological perturbations reveal that pattern-dependent susceptibility and polarized lipid organization act together to constrain isotropic waves into spatially confined, anisotropic propagation. These findings identify self-organization as a systems-level mechanism governing collective homeostasis, providing a paradigm to explore how tissue-scale organization regulates cell death in development and disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"48 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173125","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}
CellPub Date : 2026-10-15DOI: 10.1016/j.cell.2026.09.033
Min-Hwan Sohn,Danilo Dubocanin,Mitchell R. Vollger,Youngjun Kwon,Anna Minkina,Katherine M. Munson,Samuel F.M. Hart,Jane E. Ranchalis,Nancy L. Parmalee,Adriana E. Sedeño-Cortés,Jeffrey Ou,Shane J. Neph,Natalie Y.T. Au,Stephanie Bohaczuk,Brianne Carroll,Christian D. Frazar,William T. Harvey,Kendra Hoekzema,Meng-Fan Huang,Caitlin N. Jacques,Dana M. Jensen,J. Thomas Kolar,Rosa Lee,Jiadong Lin,Kelsey Loy,Taralynn Mack,Yizi Mao,Matthew W. Mitchell,Meranda M. Pham,Laura B. Scheinfeldt,Gretchen Smith,Erica Ryke,Joshua D. Smith,Lila Sutherlin,Elliott G. Swanson,Jeffrey M. Weiss,SMaHT Assembly WG,Claudia M.B. Carvalho,Tim H.H. Coorens,Kelley Harris,Chia-Lin Wei,Evan E. Eichler,Nicolas Altemose,James T. Bennett,Andrew B. Stergachis
{"title":"A telomere-to-telomere map of somatic mutation burden and functional impact in a cancer","authors":"Min-Hwan Sohn,Danilo Dubocanin,Mitchell R. Vollger,Youngjun Kwon,Anna Minkina,Katherine M. Munson,Samuel F.M. Hart,Jane E. Ranchalis,Nancy L. Parmalee,Adriana E. Sedeño-Cortés,Jeffrey Ou,Shane J. Neph,Natalie Y.T. Au,Stephanie Bohaczuk,Brianne Carroll,Christian D. Frazar,William T. Harvey,Kendra Hoekzema,Meng-Fan Huang,Caitlin N. Jacques,Dana M. Jensen,J. Thomas Kolar,Rosa Lee,Jiadong Lin,Kelsey Loy,Taralynn Mack,Yizi Mao,Matthew W. Mitchell,Meranda M. Pham,Laura B. Scheinfeldt,Gretchen Smith,Erica Ryke,Joshua D. Smith,Lila Sutherlin,Elliott G. Swanson,Jeffrey M. Weiss,SMaHT Assembly WG,Claudia M.B. Carvalho,Tim H.H. Coorens,Kelley Harris,Chia-Lin Wei,Evan E. Eichler,Nicolas Altemose,James T. Bennett,Andrew B. Stergachis","doi":"10.1016/j.cell.2026.09.033","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.033","url":null,"abstract":"Cancer genomes harbor extensive somatic genetic and epigenetic variation, yet large portions of the genome remain inaccessible to conventional reference-based analyses. Here, we demonstrate that pairing a near-telomere-to-telomere (near-T2T) diploid assembly of a donor with deep short- and long-read sequencing of their melanoma reveals that 16% of somatic variants localize to sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-associated mutagenesis. Centromere kinetochore binding domains emerge as focal sites of chromosome arm aneuploidy breakpoints and somatic genetic variation, features we further demonstrate are also present in non-cancerous tissues. By contrast, extensive epigenetic remodeling of kinetochore binding domains appears specific to oncogenesis. Single-molecule telomere analyses reconstruct the cycle of telomere erosion and telomerase-mediated extension during tumor evolution, while haplotype-resolved chromatin maps reveal widespread somatic epimutations impacting regulatory elements. Together, these findings define previously inaccessible dimensions of somatic variation and establish a framework for telomere-to-telomere studies of human mosaicism.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173086","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}
CellPub Date : 2026-10-15Epub Date: 2026-08-28DOI: 10.1016/j.cell.2026.07.053
Deepali L Kundnani, Yeunsoo Lee, Taehwan Yang, Tyler P Warner, Francisco Martinez-Figueroa, Tejasvi Channagiri, Penghao Xu, Ryan A Eckerty, Mo Sun, Supreet Randhawa, Youngkyu Jeon, Stefania Marsili, Gary Newnam, Yilin Lu, Miharu Yasumuro, Ashlesha Gogate, Vivian S Park, Sijia Tao, Justin A Ling, Ryohei Chiba, Hiroyoshi Matsumura, Ryo Uehara, Jonathan M Fogg, Lynn Zechiedrich, Raymond F Schinazi, Zachary F Pursell, Abdulmelik Mohammed, Patricia L Opresko, Bret D Freudenthal, Baek Kim, Soojin V Yi, Nataša Jonoska, Francesca Storici
{"title":"Human nuclear ribomes reveal DNA-embedded ribonucleotides as epigenetic modulators of transcription-associated DNA supercoiling.","authors":"Deepali L Kundnani, Yeunsoo Lee, Taehwan Yang, Tyler P Warner, Francisco Martinez-Figueroa, Tejasvi Channagiri, Penghao Xu, Ryan A Eckerty, Mo Sun, Supreet Randhawa, Youngkyu Jeon, Stefania Marsili, Gary Newnam, Yilin Lu, Miharu Yasumuro, Ashlesha Gogate, Vivian S Park, Sijia Tao, Justin A Ling, Ryohei Chiba, Hiroyoshi Matsumura, Ryo Uehara, Jonathan M Fogg, Lynn Zechiedrich, Raymond F Schinazi, Zachary F Pursell, Abdulmelik Mohammed, Patricia L Opresko, Bret D Freudenthal, Baek Kim, Soojin V Yi, Nataša Jonoska, Francesca Storici","doi":"10.1016/j.cell.2026.07.053","DOIUrl":"10.1016/j.cell.2026.07.053","url":null,"abstract":"<p><p>Ribonucleoside monophosphates (rNMPs) are the most abundant non-canonical nucleotides in DNA, yet their distribution and function in the human nuclear genome remain unclear. We present high-resolution maps of ∼1 million rNMPs per genome across diverse human cells, revealing a non-random nuclear \"ribome,\" the genome-wide landscape of embedded rNMPs, enriched in GC-rich regions, regulatory elements, and telomeres. Ribonucleotide-enriched zones (REZs) cluster near transcription start sites (TSSs), coincide with C-phosphate-G (CpG) islands, R-loops, and G4 structures, and scale with gene expression. Ribonuclease (RNase) H2 deficiency increases rGMP levels and is associated with topoisomerase 1 (Top1)-dependent, strand-biased rNMP enrichment near TSSs, while Top1 depletion further enhances rGMP accumulation. RNase H2-mediated nicking at rNMPs alters DNA supercoiling in vitro, and RNH2A-deficient cells show altered supercoiling at rNMP-enriched TSSs. Our findings identify embedded rNMPs as epigenetic modulators of DNA supercoiling linked to DNA sequence and transcription, revealing a connection between ribonucleotide processing and transcription-associated DNA topology in human cells.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"6648-6665.e11"},"PeriodicalIF":45.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2026-10-15DOI: 10.1016/j.cell.2026.09.044
Geraldine Maier,Manoj Hariharan,Ramesh K. Ramasamy,Aidan Glina,Laura van Rosmalen,Suraj J. Pathak,Shaunak Deota,Sahil Patel,Terry Lin,Michael Tun Yin Lam,Hiep D. Le,Krushali Powale,Takashi Shimomura,Yuta Otobe,Vince Rothenberg,Ming Sun,Takeshi Sakurai,Tiffany Chin,Yue Wu,Rosa Castanon,Anna Bartlett,Huaming Chen,Joseph R. Nery,Cesar Barragan,Swetha Devulapalli,Hemal H. Patel,Alan Saghatelian,Hikari Yoshitane,Debashis Sahoo,Susan M. Keach,Joseph R. Ecker,Satchidananda Panda
{"title":"Multi-omics atlas of chronic exercise","authors":"Geraldine Maier,Manoj Hariharan,Ramesh K. Ramasamy,Aidan Glina,Laura van Rosmalen,Suraj J. Pathak,Shaunak Deota,Sahil Patel,Terry Lin,Michael Tun Yin Lam,Hiep D. Le,Krushali Powale,Takashi Shimomura,Yuta Otobe,Vince Rothenberg,Ming Sun,Takeshi Sakurai,Tiffany Chin,Yue Wu,Rosa Castanon,Anna Bartlett,Huaming Chen,Joseph R. Nery,Cesar Barragan,Swetha Devulapalli,Hemal H. Patel,Alan Saghatelian,Hikari Yoshitane,Debashis Sahoo,Susan M. Keach,Joseph R. Ecker,Satchidananda Panda","doi":"10.1016/j.cell.2026.09.044","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.044","url":null,"abstract":"Exercise reduces all-cause mortality, yet its molecular effects across organs, sexes, and circadian phases remain incompletely understood. We subjected mice to 8 weeks of voluntary wheel running and collected 22 tissues and plasma during active and inactive phases for bulk RNA sequencing, metabolomics, proteomics, and single-nucleus RNA and methylation sequencing. Exercise induced canonical fiber-type switching and widespread, tissue-specific remodeling, with the largest transcriptomic changes in skeletal muscle. Except for the hypothalamus, kidney, and lung, most tissues changed more during the active phase. Females showed broader transcriptional responses, with distinct downregulation. Pairing single-nucleus methylomes with transcriptomes resolved the cell types driving exercise-induced epigenetic remodeling—changes undetectable by bulk studies. These included coordinated gene-body demethylation and transcription that tracked with fiber-type switching in specific myonuclei. Cell-type-resolved methylation, including partially methylated domains characterized in muscle, revealed a strong, sex-biased epigenetic response to training. Machine learning identified conserved exercise signatures across mammalian species.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"48 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173082","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}
{"title":"A pseudoenzyme sensor of trehalose-6-phosphate directly represses the metabolic integrator SnRK1 in plants","authors":"Tong Sun,Wenjuan Li,Xinyuan Liu,Kairui Li,Xiaojie Zhang,Shuanglu Xiang,Mingyang Chen,Siyu Liu,Huajian Lin,Yuwei Nian,Long Wang,Yanxia Mai,Ruiying Wang,Lizhi Zhu,Xiaoyi Wang,Yuanyuan Li,Xingzhi Li,Bowen Chen,Shanshan Wang,Yuanyuan Gao,Xiaoyan Xu,Mingliang Ye,Yiqun Geng,Jinru Zhang,Jia-Wei Wang,Weijie Huang,Minrui Fan,Ruiqiang Ye","doi":"10.1016/j.cell.2026.09.016","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.016","url":null,"abstract":"Trehalose-6-phosphate (T6P) is a central metabolic signal linking sugar availability to plant growth, carbon utilization, and productivity, yet its sensing and signaling mechanisms remain elusive. Using chemical biology and functional approaches, we identify the noncatalytic pseudoenzyme Class-II T6P synthase (TPS-II) as a T6P sensor in Arabidopsis. In the apo state, TPS-II dimerizes to form an autoinhibitory inter-subunit interaction. T6P binding to the N-terminal TPS-like domain triggers a conformational change that releases the C-terminal domain, enabling interaction with the central metabolic integrator SNF1-related protein kinase 1 (SnRK1) to repress its kinase activity. Loss of TPS-II genes activates catabolic and stress-responsive programs while suppressing anabolic gene expression, consistent with constitutive SnRK1 activity. Conservation of this T6P-TPS-II-SnRK1 signaling axis throughout the plant kingdom highlights its fundamental role in coupling carbon availability to metabolic homeostasis. These findings resolve a long-standing question in sugar signaling and provide a framework for improving crop carbon-use efficiency.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"167 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172372","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}
CellPub Date : 2026-10-13DOI: 10.1016/j.cell.2026.09.029
Boaz Styr,Kevin K. Qi,Xing Chen,William A. Liberti III,Michael M. Yartsev
{"title":"A high-dimensional population code in the bat motor cortex during natural dexterous flight","authors":"Boaz Styr,Kevin K. Qi,Xing Chen,William A. Liberti III,Michael M. Yartsev","doi":"10.1016/j.cell.2026.09.029","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.029","url":null,"abstract":"Elucidating the neural computations underlying natural, complex movement remains a fundamental challenge in neuroscience. Bat flight presents a formidable motor control challenge, requiring hand-like wings whose many degrees of freedom must be precisely coordinated to enable rapid three-dimensional (3D) maneuvers. Here, we performed large-scale wireless recordings from the wing motor cortex of freely flying bats, combined with 3D tracking of wing kinematics. Despite the complexity of flight control, bats repeatedly executed accurate flights through precise adjustments of individual wingbeats. Surprisingly, motor cortical activity was not dominated by the wingbeat cycle. Instead, neurons were sparsely active, exhibiting mixed selectivity for flight kinematics and variable entrainment to the wingbeat phase reaching millisecond-scale precision. This yielded a high-dimensional population code driven by successive wingbeats occupying distinct neural states. These findings reveal a mode of motor cortical population dynamics expressed during natural dexterous movement that is not well captured by prevailing views derived from constrained paradigms.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"53 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152687","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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