bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–09–13
seventeen papers selected by
Xiao Qin, University of Oxford
  1. A single-cell lens into the co-evolution of genotypes and phenotypes in cancer.
  2. Reflecting on 25 years of cancer research: transformative advances and unmet expectations.
  3. Reconstructing signaling histories of single cells via perturbation screens and transfer learning.
  4. A guide to understanding tumour evolution through the lens of population genetics.
  5. Mechanistic modeling reveals a configurable AP-1 network governing cell-state heterogeneity and adaptive plasticity in melanoma cells.
  6. Learning stochastic dynamics and cell-fate landscapes from single-cell snapshots via optimal transport.
  7. Monocyte-Macrophage Lineages in Cancer: Biology, Plasticity, and Therapeutic Targeting.
  8. Oncofetal reprogramming and cellular plasticity in colorectal cancer: from mechanisms to clinical translation.
  9. Rewiring Cellular Context as A Central Mechanism Governing Cancer Stem Cell Survival: Insights from ESC Comparisons.
  10. Heterotypic tumor microenvironments mirror dynamic wound-healing process.
  11. A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.
  12. scDynaBar: A Step-By-Step Experimental and Computational Guide for Time-Resolved CRISPR Barcoding at Single-Cell Resolution.
  13. MuSpAn: a toolbox for multiscale spatial analysis.
  14. Imaging cellular activity across all organs reveals body-wide circuits.
  15. Mechanisms underlying disease-causing variants in promoters and enhancers.
  16. The next 25 years of cancer research: emerging perspectives and priorities.
  17. Extracellular Matrix Remodeling in Tumors: Forces Beyond Fibroblasts.
  1. Nat Rev Cancer. 2026 Sep 08.
    A single-cell lens into the co-evolution of genotypes and phenotypes in cancer.
    Franco Izzo, Tamara Prieto, Catherine Potenski, Dan A Landau.
      Genetic heterogeneity and clonal outgrowths are observed even in otherwise healthy human tissues, shaping the genetic composition of cell populations in non-malignant disease and during physiological ageing. This clonal mosaicism likely provides the pre-cancerous seeds for malignant transformation. Once a tumour arises, clonal evolution poses a major challenge to achieving cure, as clonal diversification provides an expanded number of substrates upon which therapy can act as a selective pressure, leading to the selection of resistant clones that ultimately fuel disease recurrence. Understanding somatic clonal evolution requires not only mapping genetic diversity but also defining the resulting phenotypes that provide a fitness advantage to mutated clones. This Review discusses multimodal single-cell technologies that enable the measurement of genotypes and additional molecular features from the same cell. These technologies unveil mutant-specific phenotypic traits, often show cell-state specificity in genotype-phenotype effects and can define therapeutic vulnerabilities for precision elimination of disease-propagating mutant cells. Furthermore, the combination of phylogenetic reconstruction with phenotypic measurements allows for the temporal mapping of clonal evolution and phenotypic plasticity. These breakthroughs have created a unique opportunity to define, directly in primary human samples, the mechanisms underlying clonal expansion in both healthy and malignant tissues.
    DOI:  https://doi.org/10.1038/s41568-026-00970-8
  2. Nat Rev Cancer. 2026 Sep 08.
    Reflecting on 25 years of cancer research: transformative advances and unmet expectations.
    Allan Balmain, René Bernards, Hans Clevers, Karen H Vousden, Paul Workman, Marinka Zitnik.
      
    DOI:  https://doi.org/10.1038/s41568-026-00974-4
  3. Nat Methods. 2026 Sep 08.
    Reconstructing signaling histories of single cells via perturbation screens and transfer learning.
    Nicholas T Hutchins, Miram Meziane, Claire Lu, Maisam Mitalipova, David S Fischer, Pulin Li.
      Manipulating the signaling environment is an effective approach to alter cellular states for broad-ranging applications. Such manipulation requires knowing the signaling states and histories experienced by cells in vivo, for which high-throughput discovery methods are lacking. Here we present an integrated experimental-computational framework that learns transferable signaling response signatures from a high-throughput in vitro perturbation atlas and infers signaling activities and histories in in vivo cell types with high accuracy and temporal resolution. We generated a signaling perturbation atlas on human pluripotent stem cells and used it to train IRIS, a neural-network model. Applying IRIS to mouse embryo single-cell atlases, we uncovered global features of combinatorial signaling code usage, identified biologically meaningful heterogeneity and reconstructed signaling histories along diverse developmental lineages. This framework reveals that diverse cell types share conserved signaling response signatures, and provides a scalable solution for mapping complex signaling interactions in vivo to guide targeted interventions and enable cell fate engineering.
    DOI:  https://doi.org/10.1038/s41592-026-03213-8
  4. Nat Rev Cancer. 2026 Sep 09.
    A guide to understanding tumour evolution through the lens of population genetics.
    Giulio Caravagna, Trevor A Graham, Andrea Sottoriva.
      Every cancer carries the history of its own evolution, hidden in its genome. Modern DNA sequencing can catalogue millions of mutations and profile tumours across space and time, but sequencing alone struggles to answer the questions that matter most: when did key adaptations emerge, how strongly were they selected, why do some tumours relapse whereas others do not, and how will the cancer evolve next? The reason is fundamental: sequencing is a snapshot, whereas evolution is a dynamic process. Bridging this gap requires moving beyond descriptive cancer genomics towards quantitative evolutionary inference. In this Review, we argue that population genetics provides the mathematical framework needed to extract evolutionary dynamics from cancer genomes. We show how models of mutation, selection and drift transform allele frequencies from descriptive measurements into quantitative estimates of clonal fitness and evolutionary timings. We discuss how these principles extend to epigenetic inheritance, plasticity and ecological interactions within the tumour ecosystem, and examine the assumptions and limitations for their application to modern sequencing data. By reframing cancer genomes as quantitative records of evolutionary processes rather than catalogues of mutations, researchers have used population genetics to provide a foundation for understanding - and ultimately predicting - the trajectories of cancer evolution.
    DOI:  https://doi.org/10.1038/s41568-026-00973-5
  5. Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01043-0. [Epub ahead of print]45(9): 117965
    Mechanistic modeling reveals a configurable AP-1 network governing cell-state heterogeneity and adaptive plasticity in melanoma cells.
    Yonatan N Degefu, Magda Bujnowska, Douglas G Baumann, Mohammad Fallahi-Sichani.
      AP-1 transcription factors have been implicated in cellular plasticity, differentiation-state heterogeneity, and phenotype switching, enabling adaptation to anti-cancer therapies. Although AP-1 states, defined by the combinatorial expression of AP-1 proteins, are heterogeneous within cell populations, only a subset of possible states is observed. How these states are constrained, why their distributions vary across cell populations, and what drives their phenotypically consequential transitions remain unclear. We develop a mechanistic model of the AP-1 network, capturing dimerization-dependent, co-regulated, and competitive interactions. Calibrated to single-cell protein measurements across diverse melanoma populations and combined with statistical learning, the model reveals parameters explaining population-specific AP-1 state distributions. These parameters correlate with MAPK signaling across cell populations. The model predicts and experiments validate adaptive AP-1 reconfiguration following MAPK inhibition, driving a dedifferentiated, therapy-resistant state that is attenuated through model-guided perturbations. These findings establish AP-1 as a configurable network and provide a framework for modulating AP-1-driven cell-state plasticity.
    Keywords:  AP-1 transcription factor network; CP: cancer; cell state plasticity; computational modeling; melanoma; multiplexed; single-cell analysis; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.celrep.2026.117965
  6. Sci Adv. 2026 Sep 11. 12(37): eaeb4205
    Learning stochastic dynamics and cell-fate landscapes from single-cell snapshots via optimal transport.
    Juntan Liu, Peijie Zhou, Qing Nie, Chunhe Li.
      The temporal dynamics and stochasticity of gene expression are critical to cell fate decisions, yet integrating snapshot omics data across multiple time points remains a major challenge. Here, we introduce DiffusionOT, a dynamic machine learning framework that infers cellular trajectories from multi-time point single-cell transcriptomics by incorporating stochastic effects. DiffusionOT transforms stochastic differential equations into ordinary differential equations, using optimal transport and neural networks to solve a high-dimensional landscape model. Through an unsupervised learning of the stochastic force in the data, DiffusionOT allows robust inference of the underlying stochastic dynamics of cell-state transitions. The framework includes a stochastic trajectory analysis module for lineage tracing and a gene perturbation module for in silico knockout and overexpression experiments. Benchmarks on simulated and four real-world datasets, including a spatial Stereo-seq dataset, demonstrate DiffusionOT's accuracy and efficiency in inferring state-transition velocities, cellular trajectories, population growth, gene regulatory networks, and cell-fate landscape.
    DOI:  https://doi.org/10.1126/sciadv.aeb4205
  7. Cancer Biome Target Ther. 2026 ;1(2): 171-223
    Monocyte-Macrophage Lineages in Cancer: Biology, Plasticity, and Therapeutic Targeting.
    Christian A Owusu, Ramona Moles.
      Monocytes are highly plastic innate immune cells that serve as critical sentinels of host defense, tissue homeostasis, and inflammatory regulation. Beyond their canonical functions in phagocytosis, cytokine and chemokine production, and antigen presentation, monocytes play increasingly recognized roles in shaping the tumor ecosystem. In cancer, malignant cells and their associated stromal networks profoundly reprogram monocyte development, trafficking, and functional states, converting these cells from immune defenders into key facilitators of tumor initiation, progression, and therapeutic resistance. Upon infiltration into the tumor microenvironment (TME), circulating monocytes differentiate into heterogeneous populations of tumor-associated macrophages (TAMs) that support cancer cell survival, angiogenesis, immune suppression, and metastatic dissemination. Recent advances in single-cell transcriptomics, spatial profiling, lineage tracing, and high-dimensional cytometry have transformed our understanding of monocyte and macrophage biology, revealing previously unappreciated diversity in their ontogeny, phenotypic states, and context-dependent functions across tumor types and disease stages. These technologies have uncovered dynamic crosstalk between monocytes, TAMs, cancer cells, and other immune and stromal components, highlighting monocyte-derived populations as central regulators of the immunosuppressive TME. In this Review, we synthesize current insights into the functional heterogeneity of monocyte and macrophage subsets in cancer, emphasizing their roles in tumorigenesis, immune evasion, and therapeutic responses. We further discuss emerging therapeutic strategies aimed at targeting monocyte recruitment, differentiation, and effector functions, including macrophage reprogramming, depletion, and combinatorial approaches with immunotherapy. Collectively, these advances position monocytes and their progeny as both biomarkers and actionable targets, offering new opportunities to reshape the tumor immune landscape for durable cancer control.
    Keywords:  MDSC; TAM; cancer immunotherapy; macrophages; myeloid cells; myeloid reprogramming; myeloid-derived suppressor cells; nanomedicine; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.66505/cbtt.v1i2.23
  8. Front Oncol. 2026 ;16 1912866
    Oncofetal reprogramming and cellular plasticity in colorectal cancer: from mechanisms to clinical translation.
    Haoyu Wang, Songhao Liu, Mingxuan Zhang, Chunping Deng, Zhenguo Han.
      Colorectal cancer (CRC) progression and metastasis, as well as tolerance to therapy, are driven not only by genetic alterations but also by cell-state plasticity. Oncofetal reprogramming (OnF) refers to the reactivation of fetal intestinal developmental or injury-repair programs in tumor cells, thereby weakening adult lineage identity and enhancing the capacity for state transitions. Available evidence suggests that, in specific Wnt-dependent or APC-aberrant contexts, YAP/TAZ-TEAD and AP-1 may act cooperatively to establish and maintain the OnF state, whereas Wnt, EGFR-MAPK, FGF/FGFR, TGF-β, and extracellular matrix signaling contribute to its establishment and maintenance in a context-dependent manner. The OnF state can also intersect with epithelial-mesenchymal plasticity, dynamic stemness, drug-tolerant persister states, and immune and stromal niches, collectively increasing cellular heterogeneity, adaptability to therapy, and relapse potential in CRC. This review discusses the conceptual boundaries and operational criteria for identifying OnF in CRC, examines its regulatory mechanisms, plasticity-associated phenotypes, and translational relevance, and emphasizes the importance of distinguishing direct evidence of OnF from evidence of related plasticity mechanisms. Further elucidation of the OnF state may facilitate biomarker development and anti-plasticity therapies, although its clinical translation will require standardized state classification and clinical validation.
    Keywords:  AP-1; YAP/TAZ; cellular plasticity; colorectal cancer; drug tolerance; epithelial–mesenchymal plasticity; oncofetal reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1912866
  9. Stem Cell Rev Rep. 2026 Sep 11.
    Rewiring Cellular Context as A Central Mechanism Governing Cancer Stem Cell Survival: Insights from ESC Comparisons.
    Yasin Ahmadi, Babak Elyasi Far, Sakhavat Abolhasani.
      Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance, yet their remarkable persistence remains poorly understood. While CSCs share stemness attributes with embryonic stem cells (ESCs), including self-renewal, transcriptional plasticity, and permissive chromatin, they exhibit a fundamentally divergent regulatory logic that prioritizes survival over developmental fidelity. ESCs maintain globally open chromatin that supports transcriptional hyperactivity but predisposes them to apoptosis under genotoxic stress, whereas CSCs maintain dynamically inducible, permissive chromatin at survival loci while repressing differentiation programs, enabling adaptive stress responses. We advance the hypothesis that CSC persistence emerges not from any single factor, but from the integrative rewiring of signaling cascades (Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT/mTOR), stress-responsive transcription factors (HIFs, NF-κB, STAT3), and core pluripotency networks (OCT4, SOX2, NANOG) within a survival-centric context, reinforced by dynamic chromatin remodeling, inducible super-enhancer landscapes, and microenvironmental cues (hypoxia, inflammation, matrix stiffness). Within this framework, the E2F family serves as a key contextual integrator: in ESCs, constitutive E2F activity triggers p53-mediated apoptosis upon DNA damage, preserving genomic integrity; in CSCs, deregulated E2F activity redirects transcription toward DNA repair, antioxidant defenses, and anti-apoptotic programs. This functional divergence underscores that phenotypic outcome is determined by the broader cellular and epigenetic landscape rather than any single factor. We conclude that CSC persistence is an emergent property of this integrated, survival-centric program, fundamentally distinct from the developmental imperative of ESCs. Effective therapeutic strategies must therefore move beyond targeting individual pathways to dismantle the interconnected regulatory networks that define the CSC survival context, offering a more robust approach to overcome therapy resistance and prevent tumor relapse.
    Keywords:  Cancer Stem Cells (CSCs); Cellular context; Chromatin plasticity; E2F transcription factors; Embryonic Stem Cells (ESCs); Survival signaling; Therapy resistance
    DOI:  https://doi.org/10.1007/s12015-026-11217-2
  10. Trends Cancer. 2026 Sep 09. pii: S2405-8033(26)00203-7. [Epub ahead of print]
    Heterotypic tumor microenvironments mirror dynamic wound-healing process.
    Liqun Yu, Xiang H-F Zhang.
      Tumors co-opt normal wound-healing programs to shape their immune microenvironment, yet how distinct immune states arise and influence therapy remains unclear. Here, we synthesize emerging evidence that tumors become locked in either proinflammatory or pro-resolution phases, defined by neutrophil- or macrophage-dominated ecosystems. These states not only remodel local tissues but also systemically reprogram hematopoiesis, creating self-reinforcing immune circuits that drive progression, metastasis, and treatment resistance. We highlight recent advances linking epithelial-mesenchymal plasticity, lipid metabolism, and myeloid dynamics into an integrated 'wound-healing clock' model. This framework provides a conceptual basis for patient stratification and suggests that therapeutically redirecting immune states may unlock new strategies to overcome resistance across cancer types.
    Keywords:  myeloid plasticity; therapy resistance; tumor microenvironment; wound healing
    DOI:  https://doi.org/10.1016/j.trecan.2026.08.007
  11. Nature. 2026 Sep 09.
    A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.
    Chiara Falcomatà, Maximilian M Schaefer, Bhavya Singh, Divya Chhamalwan, Alexander Tepper, Sebastian R Nielsen, Hunter T Potak, Maxime Dhainaut, Gurkan Mollaoglu, Matthew D Park, Miriam Merad, Alessia Baccarini, Brian D Brown.
      Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1-4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.
    DOI:  https://doi.org/10.1038/s41586-026-11002-8
  12. Bio Protoc. 2026 Sep 05. 16(17): e5793
    scDynaBar: A Step-By-Step Experimental and Computational Guide for Time-Resolved CRISPR Barcoding at Single-Cell Resolution.
    Yolanda Andres-Lopez, Carla El Khouri-Gonzalez, Irene Hernando-Herraez.
      CRISPR-Cas9 barcoding technologies enable cells to record molecular events as permanent genetic changes that can be read out retrospectively. This protocol describes the implementation of a CRISPR-based recording system that gradually accumulates mutations over extended periods and is compatible with standard single-cell RNA sequencing (scRNA-seq) workflows. By temporally regulating CRISPR activity, the system generates mutational barcodes that can be captured together with individual cell transcriptomes. These barcodes are subsequently decoded using computational reconstruction approaches to infer temporal information, enabling the joint analysis of cellular states and time-resolved molecular histories. This approach provides a single-cell-compatible framework for studying dynamic biological processes in heterogeneous mouse embryonic stem cell (mESC)-derived systems, with potential extension to other biological systems. Key features • Extended temporal recording: Self-targeting guide RNAs drive progressive and cumulative barcode divergence over time. • Simultaneous barcode and transcriptome detection: Joint recovery of genetic barcodes and whole transcriptomes from the same single cell using standard scRNA-seq workflows. • In inducible scDynaBar designs: Cas9 barcode editing can be coupled to specific biological stimuli or cell-state transitions, e.g., transition of mESCs into the 2C-like state.
    Keywords:  CRISPR barcoding; Molecular clock; Mouse embryonic stem cells; Self-targeting guide RNA; Single-cell RNA-seq; Temporal recording
    DOI:  https://doi.org/10.21769/BioProtoc.5793
  13. Nat Commun. 2026 Aug 13. pii: 9737. [Epub ahead of print]17(1):
    MuSpAn: a toolbox for multiscale spatial analysis.
    Joshua A Bull, Joshua W Moore, Shania M Corry, Muyang Lin, Hayley L Belnoue-Davis, Eoghan J Mulholland-Illingworth, Simon J Leedham, Helen M Byrne.
      Advances in multiplex imaging and spatial omics have revolutionised spatial data generation in biology, revealing complex tissue organisation across multiple scales. However, methods for analysing these data have lagged behind, with fragmented, study-specific pipelines and limited guidance for tool selection. To address this, we introduce MuSpAn, a Multiscale Spatial Analysis package offering intuitive, flexible access to a wide range of mathematical tools - including spatial statistics, topological data analysis, geometry, and networks - within a unified framework. MuSpAn supports efficient data querying, is agnostic to imaging modality, and provides extensive documentation and community support. It enables users to create custom pipelines or conduct unbiased exploratory analyses. We demonstrate MuSpAn's capacity to interrogate cross-compartmental cell interactions at multiple length scales in both normal and neoplastic tissue using mouse intestinal spatial transcriptomic datasets. Applied to a CMS4-like murine intestinal cancer model, MuSpAn identifies a continuum of fibroblastic functional phenotypes associated with discrete and coordinated fibroblast-immune interactions, highlighting its utility as a discovery tool across diverse biological contexts.
    DOI:  https://doi.org/10.1038/s41467-026-75649-7
  14. Nature. 2026 Sep 09.
    Imaging cellular activity across all organs reveals body-wide circuits.
    Virginie M S Ruetten, Wei Zheng, Igor Siwanowicz, Brett D Mensh, Mark Eddison, Amy Hu, Yunfeng Chi, Andrew L Lemire, Caiying Guo, Mykola Kadobianskyi, Marc Renz, Sara Lelek-Greskovic, Yisheng He, Kari Close, Gudrun Ihrke, Aparna Dev, Alyson Petruncio, Yinan Wan, Rongwei Zhang, Mark C Fishman, Florian Engert, Benjamin Judkewitz, Mikail Rubinov, Philipp J Keller, Chie Satou, Guoqiang Yu, Paul W Tillberg, Maneesh Sahani, Misha B Ahrens.
      An animal's ability to survive and thrive-whether fleeing from danger, eating a meal, or fighting an infection-arises from the collective moment-to-moment activity of many interacting cell types throughout the body. Physiology seeks to elucidate these cellular interactions that span organs, cell types and timescales, but has been limited by the inability to record this time-varying cellular activity simultaneously throughout the entire body. Here we develop WHOLISTIC (WHole-Organism Live-Imaging System for recording Tissue and IntraCellular activity), a method to image second-timescale activity of cells across the entire vertebrate body at cellular resolution. WHOLISTIC advances and integrates volumetric fluorescence microscopy, machine learning, and pancellular transgenic expression of calcium sensors1, demonstrated in larval zebrafish, with proof of concept in adult Danionella cerebrum. To access information about the molecular and ultrastructural substrates for the measured dynamics, we advanced whole-body expansion microscopy2. At the cellular scale, body-wide screening revealed unexpected responses, including chondrocyte reactions to cold and meningeal responses to ketamine. At the organ scale, WHOLISTIC identified rhythmic travelling waves along the renal nephron. At the multi-organ scale, it revealed unknown muscle synergies and muscle-organ interactions. At the whole-organism scale, the method captured brainstem-controlled redistribution of body-wide blood flow. Combining optogenetics with WHOLISTIC enabled all-optical causal dissection of brain-body interactions. These advances establish a paradigm for systems biology that bridges cellular and organismal physiology, enabling comprehensive discovery across scales-from fundamental mechanisms to therapeutic targets.
    DOI:  https://doi.org/10.1038/s41586-026-10979-6
  15. Nat Genet. 2026 Sep 08.
    Mechanisms underlying disease-causing variants in promoters and enhancers.
    Hannah K Long, Kun Wu, Ryan S Barkham, Wendy A Bickmore.
      The study of human monogenic disorders has been a powerful tool for generating a deep understanding of protein function/dysfunction and for uncovering underlying biological mechanisms. Here we explore the insights that an expanding catalog of noncoding monogenic disease variants can provide into the functions of the noncoding genome. We focus on small genetic alterations (one to a few tens of base pairs) in cis-regulatory elements-promoters, enhancers and silencers-and their potential mechanisms of action, such as loss or gain of function. We discuss the challenges in determining pathogenicity for variants in the noncoding genome, discuss why there might be so few concrete examples and highlight the opportunities for advancing this area of human genetics by using experimental and machine-learning tools.
    DOI:  https://doi.org/10.1038/s41588-026-02743-3
  16. Nat Rev Cancer. 2026 Sep 07.
    The next 25 years of cancer research: emerging perspectives and priorities.
    Myriam Chalabi, Tim H H Coorens, Leanne Li, James L Reading, Shensi Shen, Ewa Szczurek.
      
    DOI:  https://doi.org/10.1038/s41568-026-00975-3
  17. Cancer Res. 2026 Sep 08.
    Extracellular Matrix Remodeling in Tumors: Forces Beyond Fibroblasts.
    Sonal Srivastava, Alyaa Dawoud, Andrew C Dudley, Mitsuo Yamauchi, Chad V Pecot, Antonio L Amelio.
      Aberrant extracellular matrix (ECM) remodeling in tumors is characterized by altered deposition, enzymatic cross-linking, degradation, and organization of matrix molecules that in turn can contribute directly to tumor invasiveness, immune evasion, and resistance to therapy. Traditionally, cancer-associated fibroblasts (CAFs) have been considered the principal architects of ECM remodeling in tumors. However, the role of non-fibroblast cell populations in modulating ECM structure and function and how these processes intersect with immune regulation, metabolism, and metastasis is also crucial but currently underappreciated. Challenging the prevailing fibroblast-centric paradigm, this review provides an overview of how non-fibroblast cell types engage in dynamic crosstalk and collectively shape the biochemical and biomechanical landscape of tumors. Therapeutic strategies targeting these alternative stromal players could disrupt pro-tumor ECM dynamics, enhance anti-tumor immunity, and restore tissue homeostasis. Thus, a comprehensive understanding of the intricate network of non-fibroblast stromal cells within the tumor microenvironment (TME) can help elucidate opportunities for precision medicine and personalized cancer care, leading to the development of innovative therapeutic interventions targeting the TME.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1532
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