Proceedings of the National Academy of Sciences of the United States of America最新文献_第7页

Efficient and accurate steering of large language models through attention-guided feature learning. 通过注意引导特征学习高效准确地控制大型语言模型。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-16 DOI: 10.1073/pnas.2609978123

Parmida Davarmanesh, Ashia Wilson, Adityanarayanan Radhakrishnan

{"title":"Efficient and accurate steering of large language models through attention-guided feature learning.","authors":"Parmida Davarmanesh, Ashia Wilson, Adityanarayanan Radhakrishnan","doi":"10.1073/pnas.2609978123","DOIUrl":"https://doi.org/10.1073/pnas.2609978123","url":null,"abstract":"Activation steering, or direct manipulation of internal activations to guide large language model (LLM) responses toward specific semantic concepts, is emerging as a promising avenue for both understanding how semantic concepts are stored within LLMs and advancing LLM capabilities. Yet, existing steering methods are remarkably brittle, with seemingly nonsteerable concepts becoming completely steerable based on subtle algorithmic choices in how concept-related features are extracted. In this work, we introduce an attention-guided framework for activation steering that overcomes three core challenges associated with steering: 1) automatic selection of relevant token embeddings for extracting concept-related features; 2) accounting for heterogeneity of concept-related features across LLM activations; and 3) identification of layers most relevant for steering. Across a steering benchmark of 512 semantic concepts, our framework substantially improved steering over previous state-of-the-art (nearly doubling the number of successfully steered concepts) across model architectures and sizes (up to 70 billion parameter models). Furthermore, we use our framework to shed light on the distribution of concept-specific features across LLM layers. Overall, our framework opens further avenues for developing efficient, highly scalable fine-tuning algorithms for industry-scale LLMs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2609978123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Autoimmunity induced by epigenome alteration affecting thymic Treg cell development. 影响胸腺Treg细胞发育的表观基因组改变诱导的自身免疫。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-14 DOI: 10.1073/pnas.2626262123

Jia Long, Jun Huang, Masaya Arai, Yamami Nakamura, Norihisa Mikami, Kenji Ichiyama, Shimon Sakaguchi

{"title":"Autoimmunity induced by epigenome alteration affecting thymic Treg cell development.","authors":"Jia Long, Jun Huang, Masaya Arai, Yamami Nakamura, Norihisa Mikami, Kenji Ichiyama, Shimon Sakaguchi","doi":"10.1073/pnas.2626262123","DOIUrl":"https://doi.org/10.1073/pnas.2626262123","url":null,"abstract":"Methyl-CpG-binding domain protein 3 (MBD3), an essential component of the nucleosome remodeling and deacetylase (NuRD) complex, controls chromatin accessibility at lineage-specific transcriptional enhancers and promoters during hematopoietic cell differentiation. Here, we have shown that MBD3 deficiency in the T cell compartment resulted in spontaneous development of T cell-mediated multiorgan autoimmune diseases including fatal autoimmune myocarditis. The MBD3-deficient mice notably showed a significant reduction of CD25+Foxp3+ regulatory T (Treg) cells in both the thymus and periphery without much affecting the development and function of conventional T (Tconv) cells. Mixed bone marrow (BM) chimeras reconstituted with wild-type and MBD3-deficient BM revealed a cell-intrinsic defect in thymic Treg cell lineage differentiation in MBD3-deficient cells. Transcriptional, phenotypic, and functional analyses of thymocyte subsets further revealed that MBD3 deficiency particularly affected the activation of a Treg-specific enhancer of the Il2ra gene encoding CD25, hence impaired CD25 expression in immature CD4 single-positive thymocytes (ImCD4SP) but not in peripheral T cells. The impairment markedly limited thymic Treg precursor cell generation and substantially reduced overall thymic Treg cell output. By contrast, MBD3 deficiency scarcely impacted the TGF-β/IL-2-dependent in vitro Treg cell generation from Tconv cells. Thus, Treg-specific developmental properties such as high IL-2/CD25 dependency of their thymic differentiation may render them more sensitive than Tconv cells to epigenetic changes of the whole T cell compartment. The results provide a mechanistic basis by which general epigenomic alterations in the T cell compartment can be causative of autoimmune and other immunological diseases through selectively affecting thymic Treg cell development.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2626262123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Field experiments predict ecological response to a large-scale epidemic of an anti-keystone pathogen. 野外试验预测生态反应对大规模流行的抗基斯通病原体。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-12 DOI: 10.1073/pnas.2529492123

J Timothy Wootton, Khashiff Miranda, Amy K Henry, Catherine A Pfister

{"title":"Field experiments predict ecological response to a large-scale epidemic of an anti-keystone pathogen.","authors":"J Timothy Wootton, Khashiff Miranda, Amy K Henry, Catherine A Pfister","doi":"10.1073/pnas.2529492123","DOIUrl":"https://doi.org/10.1073/pnas.2529492123","url":null,"abstract":"Knowledge of how pathogens, in the context of a changing environment, shape the structure of ecological communities remains limited, and little information exists on the ability of small-scale field experiments to predict the consequences of large-scale environmental impacts. We addressed these issues using the emergence of a widespread epidemic (sea star wasting disease, SSWD) on rocky intertidal shorelines. Prior experiments demonstrated strong reductions in sessile species diversity in response to the local experimental removal of the sea star Pisaster ochraceus [R. T. Paine, Am. Nat. 100, 65-75 (1966); R. T. Paine, Oceologia 15, 93-120 (1974)] at our site. In surveys of sea star populations over 8 y spanning the onset of the SSWD epidemic, P. ochraceus populations declined by 90%, then subsequently recovered to about one third of pre-epidemic size under an endemic disease phase. Using four different types of temporal data, we documented large increases in populations of the competitively dominant mussel Mytilus californianus following P. ochraceus decline, which were of similar magnitude to those observed in prior field experiments. As in the field experiments, sessile species richness and diversity declined strongly following the onset of the SSWD epidemic as mussels were released from predator control. Our results reveal a strong effect of a pathogen in regulating ecological community structure by disrupting the role of a keystone species, a result anticipated by prior small-scale field experiments.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2529492123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multiyear dual-isotope fingerprinting at South Asian receptor sites constrains carbon monoxide sources and enhanced oxidation. 南亚受体位点的多年双同位素指纹图谱限制了一氧化碳源和增强的氧化。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-12 DOI: 10.1073/pnas.2606200123

Peng Yao, Henry Holmstrand, Carina van der Veen, Maria Elena Popa, Chloe A Brashear, Krishnakant Budhavant, Mohanan Remani Manoj, Joakim Romson, Abdus Salam, Thomas Röckmann, Örjan Gustafsson

{"title":"Multiyear dual-isotope fingerprinting at South Asian receptor sites constrains carbon monoxide sources and enhanced oxidation.","authors":"Peng Yao, Henry Holmstrand, Carina van der Veen, Maria Elena Popa, Chloe A Brashear, Krishnakant Budhavant, Mohanan Remani Manoj, Joakim Romson, Abdus Salam, Thomas Röckmann, Örjan Gustafsson","doi":"10.1073/pnas.2606200123","DOIUrl":"https://doi.org/10.1073/pnas.2606200123","url":null,"abstract":"Carbon monoxide (CO) is an indirect short-lived climate forcer with uncertainties both in sources and its role in atmospheric oxidation. Based on nine winter-long dual-isotope campaigns at two South Asian receptor sites intercepting the continental outflow, we quantified CO source contributions and emission-sink dynamics. Combustion accounts for 68 to 74% of South Asia regional CO (including 34 to 37% from biomass burning) with secondary atmospheric oxidation contributing 26 to 32% (dominated by oxidation of nonmethane volatile organic compounds (NMVOCs) at 21 to 26%, with methane oxidation contributing 5.5 to 6.4%). These isotope-observational constraints suggest a twice higher role for atmospheric oxidation than in model estimates. Spatially, the absolute contributions of both primary and secondary CO decrease from the Indo-Gangetic Plain to the northern Indian Ocean, while the relative contribution of oxidation-derived CO increases, indicating enhanced secondary CO production near source regions. Observation-model comparison suggests that transport from the continental areas dominates CO over adjacent oceanic regions, with minor local production. During the COVID-19 emission perturbation, combustion-derived CO fell sharply in absolute terms, NMVOC-derived CO rose, and CH4-derived CO remained stable, providing an observational constraint on the sensitivity of atmospheric oxidation to emission changes. Our results reveal a significant contribution of CO from atmospheric oxidation in South Asia, calling for a reassessment of regional emission-oxidation coupling in models and of mitigation strategies.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2606200123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery and characterization of miranthins, "Trojan horse" antibiotic modulators of bacterial composition in the oral microbiome. miranthins的发现和表征，“特洛伊木马”抗生素调节剂的细菌组成在口腔微生物组。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-12 DOI: 10.1073/pnas.2621138123

Brielle E Dalvano, Brett C Covington, Mohammad R Seyedsayamdost

{"title":"Discovery and characterization of miranthins, \"Trojan horse\" antibiotic modulators of bacterial composition in the oral microbiome.","authors":"Brielle E Dalvano, Brett C Covington, Mohammad R Seyedsayamdost","doi":"10.1073/pnas.2621138123","DOIUrl":"https://doi.org/10.1073/pnas.2621138123","url":null,"abstract":"Bacteria of the human microbiota encode an abundance of natural products that likely mediate bacterial competition, local colonization patterns, and human health and disease. However, very few of these compounds have been identified and characterized to date. During our investigation of Streptococcus mitis, an important early colonizer of the oral cavity, we identified and structurally characterized a family of peptide natural products, termed miranthins herein, that contain an unusual macrocycle formed by an Asp-Cys β-carbon thioether crosslink. We determined that the most abundantly secreted miranthin is a \"Trojan horse\" antibiotic that enters sensitive cells via the Ami oligopeptide transporter, is hydrolyzed and activated by aminopeptidase N, and subsequently inhibits ribosomal translation to curb the growth of streptococcal competitors. The miranthins are narrow-spectrum antibiotics that could enable S. mitis to modulate community dynamics in the oral cavity, highlighting the importance of peptide natural products in interspecies competition in the microbiome.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2621138123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca²⁺ transfer and signaling in Trypanosoma cruzi. 克氏锥虫中Piezo2的膜接触激活驱动溶酶体-线粒体Ca2+转移和信号传导。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-16 DOI: 10.1073/pnas.2627551123

Guozhong Huang, Roberto Docampo

{"title":"Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.","authors":"Guozhong Huang, Roberto Docampo","doi":"10.1073/pnas.2627551123","DOIUrl":"https://doi.org/10.1073/pnas.2627551123","url":null,"abstract":"Calcium ion (Ca2+) transfer from other organelles is central to mitochondrial metabolism and cell survival, yet how mechanical forces regulate interorganelle communication remains unclear. Here we report a lysosome-to-mitochondrion pathway in Trypanosoma cruzi, the etiologic agent of Chagas disease, mediated by the mechano/osmosensitive channel TcPiezo2. Using ultrastructural, biochemical, and live-cell superresolution imaging, we define lysosome-mitochondrion contact sites (LMCs) that enable direct Ca2+ transfer. TcPiezo2 triggers Ca2+ release, which generates perilysosomal nanodomains that drives mitochondrial Ca2+ uptake via the voltage-dependent anion channel and the mitochondrial Ca2+ uniporter complex. Disruption of TcPiezo2-dependent Ca2+ transfer impairs mitochondrial metabolism, perturbs redox homeostasis, induces autophagy, and eventually leads to parasite death. These findings establish LMCs as a signaling platform that directly regulates interorganelle Ca2+ transfer and mitochondrial bioenergetics.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2627551123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A transposon inserted into HELD1 repressed maize husk leaf blade extension during maize domestication. 在玉米驯化过程中，插入HELD1的转座子抑制玉米外壳叶片的延伸。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-16 DOI: 10.1073/pnas.2602491123

Xing Jian, Li Dong, Xuan Zhang, Ankush Sangra, Zongliang Chen, Jiacheng Liu, Yang Song, Guorui Fan, Le Xu, Tianyu Feng, Min Xu, Qianwen Zhang, Yiwen You, Zhaoying Wang, Robert J Schmitz, Andrea Gallavotti, Zhongwei Lin

{"title":"A transposon inserted into HELD1 repressed maize husk leaf blade extension during maize domestication.","authors":"Xing Jian, Li Dong, Xuan Zhang, Ankush Sangra, Zongliang Chen, Jiacheng Liu, Yang Song, Guorui Fan, Le Xu, Tianyu Feng, Min Xu, Qianwen Zhang, Yiwen You, Zhaoying Wang, Robert J Schmitz, Andrea Gallavotti, Zhongwei Lin","doi":"10.1073/pnas.2602491123","DOIUrl":"https://doi.org/10.1073/pnas.2602491123","url":null,"abstract":"Husk leaves are the closest photosynthetic organs to the ear, which contribute directly to grain filling and have potential for yield improvement in maize. Teosinte has a long husk extended leaf blade, whereas maize exhibits a reduced or even no husk leaf blade. However, the genetic basis of this transition in the husk leaf during domestication remains unknown. In this study, we identified a major quantitative trait locus (QTL), Husk Extended Leaf Blade 1 (HELD1), corresponding to the tassels replace upper ears1 (tru1) gene. A 133-base pair (bp) Harbinger transposon inserted into the tru1 intron introduces two TEOSINTE BRANCHED 1 (TB1) binding motifs, thereby recruiting TB1 to directly enhance tru1 transcription. Further analyses revealed that TRU1 interacts with the transcription factor ALOG1, which in turn enhances the expression of liguleless2 (lg2), a key regulator of ligule development. Together with brassinosteroid-deficient dwarf1 (brd1) and GA2ox1, these genes set up a regulatory network that defines the ligular-auricular position, controls the leaf blade-to-husk (sheath) ratio in husk and stem leaves, and regulates husk leaf blade length. Population genetic analyses indicate that HELD1 experienced significant human selection, resulting in the transposon insertion becoming the dominant allele in domesticated maize. Additionally, the teosinte HELD1 allele with extended husk leaf blades significantly enhances yield in maize. Our results demonstrate HELD1 is an important regulator of husk and stem leaf architectures, contributing to the ligular-auricular position to adjust the ratio of leaf blade to husk or sheath.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2602491123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Systemic collapse emergence from climate-induced perturbations in transportation networks. 由气候引起的交通网络扰动引起的系统崩溃。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-16 DOI: 10.1073/pnas.2532180123

Mauro Faccin, Tomas Scagliarini, Manlio De Domenico

{"title":"Systemic collapse emergence from climate-induced perturbations in transportation networks.","authors":"Mauro Faccin, Tomas Scagliarini, Manlio De Domenico","doi":"10.1073/pnas.2532180123","DOIUrl":"https://doi.org/10.1073/pnas.2532180123","url":null,"abstract":"The interaction between human infrastructures and external events results in loss of functionality or even complete system disruption through a snowball effect of cascading failures. Their complex interplay challenges their prevention, affecting the human population that rely on their functionality. Understanding how these networks respond to external perturbations is crucial for predicting and mitigating the impacts of disruptive events. In particular, meteorological events, while not preventable, can have significant impacts on human infrastructure. Here, we propose a model coupling the dynamics of transportation systems to the dynamics of external events considered as fields, to capture at the same time the critical behavior of the former and the level of influence of the latter. The impact of rainfalls on real-world railway networks provides a compelling case study, showcasing local endemic and system-wide disruptions above a critical value of the rainfall strength. Remarkably, localized perturbations on the wider network reveals the local weaknesses of the global infrastructure, and we assess them in terms of system perturbability and corresponding societal risk. Our framework opens the door to the quantitative analysis of criticalities in essential human infrastructure imputable to vulnerabilities that are set to intensify due to climate change.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2532180123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ecology must shape AI before AI reshapes ecology. 生态必须在人工智能重塑生态之前塑造人工智能。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-09 DOI: 10.1073/pnas.2619925123

George Roff

引用次数: 0

Cell identity competes with surface tension to determine stromal organization in tumor spheroids beyond the CAF shell paradigm. 细胞身份与表面张力竞争，以确定肿瘤球体中CAF壳范式之外的基质组织。

IF 9.5 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2026-10-20 Epub Date: 2026-10-12 DOI: 10.1073/pnas.2624455123

Claire Wilhelm

{"title":"Cell identity competes with surface tension to determine stromal organization in tumor spheroids beyond the CAF shell paradigm.","authors":"Claire Wilhelm","doi":"10.1073/pnas.2624455123","DOIUrl":"https://doi.org/10.1073/pnas.2624455123","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) are often found forming a peripheral stromal barrier around tumors. Here, this paradigm is challenged using microfabricated 3D cancer-CAF spheroid models combined with quantitative magnetic force tensiometry. A surface tension atlas is established for eight cancer cell lines, three CAF populations, and heterotypic tumor-CAF assemblies, spanning nearly two orders of magnitude. Surface tension is first shown to govern spheroid morphology and modulate drug response. Besides, CAFs consistently occupy the highest end of the surface tension hierarchy, predicting core rather than peripheral localization and directly challenging the shell paradigm. Yet confocal imaging reveals not only central accumulation but also complete CAF-tumor mixing, including in spheroids where cancer cells exhibit surface tensions nearly two orders of magnitude lower than CAFs. Surface tension alone therefore fails to predict CAF organization. Instead, the epithelial-to-mesenchymal transition (EMT) state of cancer cells emerges as a major determinant: epithelial-like tumors promote CAF core accumulation, whereas mesenchymal-like states favor persistent mixing. Peripheral CAF localization emerges only under restricted conditions combining high tumor cohesion and sequential stromal recruitment. Together, these results identify surface tension, EMT state, and assembly chronology as joint determinants of tumor-stroma architecture, revealing a context-dependent organization landscape rather than a universal CAF shell.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2624455123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0