CellPub Date : 2026-10-15DOI: 10.1016/j.cell.2026.09.046
Jacey R. Pridgen,Margaret A. Goodell
{"title":"Charting the silent variation within us","authors":"Jacey R. Pridgen,Margaret A. Goodell","doi":"10.1016/j.cell.2026.09.046","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.046","url":null,"abstract":"Every cell in the human body carries its own genome, shaped by mutations acquired over a lifetime, yet this vast somatic variation has been nearly impossible to measure. The SMaHT Network now delivers benchmarked tools and the first body-wide map of somatic mosaicism, establishing a baseline of “normal” against which its roles in development, aging, and disease can finally be tested.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"21 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173089","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":"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.2026.09.043
Jack M. Moen,Alicia L. Richards,Einar K. Krogsaeter,Benjamin J. Polacco,Martin Gordon,Erica Stevenson,Rhiana Boyles,Maximilien Burq,Dejan Stepec,Bryan Crampton,Nathaniel Sin,Zachary Gale-Day,Jason E. Gestwicki,Peter Cimermancic,Joshua J.C. Rosenthal,Nevan J. Krogan,Danielle L. Swaney
{"title":"Functional diversification of the cephalopod proteome by RNA editing","authors":"Jack M. Moen,Alicia L. Richards,Einar K. Krogsaeter,Benjamin J. Polacco,Martin Gordon,Erica Stevenson,Rhiana Boyles,Maximilien Burq,Dejan Stepec,Bryan Crampton,Nathaniel Sin,Zachary Gale-Day,Jason E. Gestwicki,Peter Cimermancic,Joshua J.C. Rosenthal,Nevan J. Krogan,Danielle L. Swaney","doi":"10.1016/j.cell.2026.09.043","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.043","url":null,"abstract":"Coleoid cephalopods exhibit the highest levels of adenosine deaminases acting on RNA (ADAR)-mediated RNA editing of any known taxon, yet the functional consequences of most recoding events remain unclear. Here, we integrated proteomics with biochemical and cellular assays to characterize recoding across the Doryteuthis pealeii proteome. This confirmed the translation of 7,997 recoded sites at the protein level and revealed how recoding reshapes the proteome by altering protein stability, subcellular localization, post-translational modifications, and enzymatic activity. We find that recoding also creates or ablates post-translational modification sites, with direct effects on protein function and protein-protein interactions. Recoding the E3 ligase MARCHF5 drives widespread changes in substrate ubiquitylation and perturbs mitochondrial homeostasis, illustrating how RNA editing can influence organelle function. Together, these data give a proteome-scale view of how extensive RNA recoding diversifies protein function in coleoid cephalopods and offer a framework for understanding how RNA-level plasticity shapes protein function and cellular physiology.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"33 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173083","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.2026.09.010
Dan Corral,Yasmine Belkaid
{"title":"Milking the niche: Microbial control of neonatal hematopoiesis","authors":"Dan Corral,Yasmine Belkaid","doi":"10.1016/j.cell.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.010","url":null,"abstract":"In this issue of Cell, Howard et al. reveal how the milk glycoprotein osteopontin shapes the neonatal microbiome to regulate hematopoiesis, promoting dendritic cell development and protection from severe respiratory infection. These findings uncover a maternal milk-microbiota pathway linking early-life nutrition to immune development and long-term disease susceptibility.","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":"149173091","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.2026.09.040
Zijian Pan,Ming-Kwan Wong,Yang Lu,Jingxuan Mao,Fengxiang Wang,Xin Gu,Kaiyin Huang,Taotao Shi,Tianshu William Wu,Yuxuan Zhu,Yuan Zhang,En Chen,Jingrong Regina Han,Yunfei Qiu,Lei Zhou,Yinxin Li,Peng Lin,Zhibin Li,Shan Deng,Yingshan Fang,Qi Xie,Jian Cao,Nathchar Naowarojna,Dan Yang,Yilong Zou
{"title":"Mitochondria-targeted tetraoxanes initiate lipid peroxidation to drive ferroptosis and tumor suppression","authors":"Zijian Pan,Ming-Kwan Wong,Yang Lu,Jingxuan Mao,Fengxiang Wang,Xin Gu,Kaiyin Huang,Taotao Shi,Tianshu William Wu,Yuxuan Zhu,Yuan Zhang,En Chen,Jingrong Regina Han,Yunfei Qiu,Lei Zhou,Yinxin Li,Peng Lin,Zhibin Li,Shan Deng,Yingshan Fang,Qi Xie,Jian Cao,Nathchar Naowarojna,Dan Yang,Yilong Zou","doi":"10.1016/j.cell.2026.09.040","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.040","url":null,"abstract":"Ferroptosis is implicated as a vulnerability in multiple cancers, yet approaches for effectively inducing ferroptosis in vivo are limited. Bypassing conventional strategies targeting the antiferroptotic glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) proteins, we designed metabolic initiators of lipid peroxidation (MILPOs) and developed the compounds WMK-1/2, which contain tetraoxane radical-generating and mitochondria-targeting groups, as de novo ferroptosis inducers. WMK-1 localizes primarily to mitochondria, induces local lipid peroxidation, and impairs oxidative phosphorylation. WMK-1 induces a “mito-ferroptosis” sub-pathway that skips GPX4 inhibition as a prerequisite, can be rescued by lipophilic radical-trapping antioxidants, yet is minimally sensitive to acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) perturbation and long-chain polyunsaturated fatty acid (PUFA) supplementation, and evades retinol-mediated protection. Instead, WMK-1-induced cell death requires labile Fe2+ and can be selectively suppressed by ɑ-lipoic acid, an endogenous, mitochondria-resident antioxidant. WMK-1/2 are bioavailable and exhibit significant efficacy in tumor suppression by eliciting ferroptosis in multiple cancer models and augmenting the antitumor effects of immune-checkpoint blockers. Our work provides a protein-targeting-independent metabolic ferroptosis induction strategy for potential cancer therapy.","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":"149173123","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}
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