bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–04–26
seventeen papers selected by
Xiao Qin, University of Oxford
  1. High-throughput histopathology for complex in vitro models.
  2. Pathophysiological roles of monocytes and macrophages in cancer.
  3. Epithelial-to-mesenchymal transition as a central driver of tumor cell plasticity.
  4. Early fibrotic niches establish tumour-permissive microenvironments.
  5. Heterogeneity and plasticity of cancer-associated fibroblasts.
  6. Decoding the CAF-TAM axis: multi-omics dissection and therapeutic targeting of stromal-immune crosstalk in the tumor microenvironment.
  7. TimeVault: a synthetic time capsule for transcriptome storage.
  8. Cancer signaling beyond the genes.
  9. The sleeping threat: targeting cancer dormancy to transform metastasis therapy.
  10. Network analysis to understand gene regulation: across spatial scales and toward multi-level models.
  11. From inflammation to malignancy: the dynamic evolution of cancer-associated fibroblasts in IBD-CRC.
  12. Wikipedia-based AI model reveals the 100 technologies to watch.
  13. Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.
  14. Microbiota-derived metabolites as modulators of cancer immunotherapy response.
  15. Beyond the Transcriptome: Leveraging Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) for Deeper Cellular Insights.
  16. LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.
  17. Emerging biomarkers for early detection of colorectal cancer.
  1. Cell Rep Methods. 2026 Apr 23. pii: S2667-2375(26)00119-0. [Epub ahead of print] 101419
    High-throughput histopathology for complex in vitro models.
    Marius F Harter, Elisa D'Arcangelo, Julien Aubert, Barbora Lavickova, Charles Havnar, Bilgenaz Stoll, Irineja Cubela, Adrian M Filip, Laura Gaspa-Toneu, Julian Scherer, Evdoxia Karagkiozi, Jean-Samuel Dupré, Rubén López-Sandoval, Rebecca Hsia, Leah M Norona, Giovanna Brancati, Ryo Okuda, J Gray Camp, Eliah R Shamir, Jose Luis Garcia-Cordero, Iago Pereiro, Nikolche Gjorevski.
      Histology has been a cornerstone for complex in vitro model (CIVM) characterization for decades. However, it remains a low-throughput method with time-consuming workflows. Here, we introduce a holistic "histo-workflow," utilizing 3D-printed histomolds that facilitate co-planar embedding of CIVMs at high throughput, resulting in up to 80 samples in one section. We developed a variety of model-specific histomold designs that enable spatially controlled histological sectioning and downstream analyses. We describe these workflows, including mold generation, high-plex staining, and image analysis, and exemplify their application to histological analyses of various CIVMs. Altogether, the histomolds introduced here afford opportunities for CIVM processing and analysis, while significantly reducing labor and reagent resources, thereby democratizing high-throughput handling of CIVMs in histopathology.
    Keywords:  CP: imaging; CP: stem cell; FFPE; embedding of complex in vitro models; high-throughput embedding; histopathology; immunohistochemistry; microarrayed tissues; multiplex immunofluorescence; organoid FFPE sections; organoids
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101419
  2. Nat Rev Immunol. 2026 Apr 20.
    Pathophysiological roles of monocytes and macrophages in cancer.
    Liangliang Ji, Jiaxin Li, Ting-Wei Hsu, Ming O Li.
      Monocytes and macrophages are versatile immune sentinels that are present in nearly all tissues, where they continually adapt to local cues. In cancer, their functions are context-dependent - often linked to tumour growth and poor prognosis but also capable of driving potent antitumour immunity. To explain this dichotomy, we frame cancer cells as 'infectious self', having both pathogen-like and self-like features. In turn, monocytes and macrophages adopt modular programmes across primary and metastatic tumour sites - as well as along haematogenous, lymphatic and transcoelomic routes of dissemination - that are shaped by oncogenic lesions, cancer cell differentiation states, tissue perturbations and organism-level variables. These cells are promising yet challenging therapeutic targets. Opportunities include blocking the recruitment, differentiation and scavenging activity of pro-tumour monocytes and macrophages; activating pattern recognition receptor signalling pathways and lymphocyte help; inducing cancer cell phagocytosis; and rewiring key intracellular signalling nodes. Emerging cellular and gene-based approaches - such as chimeric receptor engineering and in vivo target delivery - further expand this toolkit and underscore the potential to reprogramme monocyte and macrophage responses for durable control of solid tumours.
    DOI:  https://doi.org/10.1038/s41577-026-01296-0
  3. Nat Cancer. 2026 Apr 24.
    Epithelial-to-mesenchymal transition as a central driver of tumor cell plasticity.
    Raul Jimenez-Castaño, M Angela Nieto.
      Epithelial-to-mesenchymal transition (EMT) is a central driver of cancer cell plasticity, enabling invasion, immune evasion, therapeutic resistance and metastasis. Rather than a binary switch, EMT comprises a continuum of transient, reversible states that endow tumor cells with distinct functional properties. Recent technological advances have revealed an unexpected diversity of EMT states across tumor contexts, with implications for disease progression and therapy response. In this Review, we synthesize emerging evidence on EMT heterogeneity and dynamics during cancer progression, examine how new methodologies have increased our understanding of the process and outline therapeutic challenges and opportunities.
    DOI:  https://doi.org/10.1038/s43018-026-01154-x
  4. Nature. 2026 Apr 22.
    Early fibrotic niches establish tumour-permissive microenvironments.
    Erik C Cardoso, Hyeyoung Lee, Frances J England, Hyunjin Cho, Robin Lu, Sagar S Varankar, Moo Suk Park, Natasha Rekhtman, Bon-Kyoung Koo, Benjamin D Simons, Jinwook Choi, Joo-Hyeon Lee.
      Pathologic transformation represents a critical yet poorly defined window during which mutant epithelial stem cells actively construct the microenvironment that enables tumour initiation1,2. Here using integrated single-cell, spatial and functional analyses, we define the earliest multicellular events that licence this transition following oncogenic activation in the lung. KrasG12D-mutant alveolar type II cells rapidly adopt regenerative-like states that act as signalling hubs, orchestrating coordinated stromal and immune reprogramming while enhancing epithelial plasticity. Through secretion of amphiregulin, mutant epithelial cells activate EGFR signalling in adjacent fibroblasts, inducing a fibrotic, injury-like programme. Reprogrammed fibroblasts, in turn, expand and reprogramme alveolar macrophages, amplifying inflammatory signalling and reinforcing epithelial plasticity. These reciprocal interactions establish a self-sustaining epithelial-stromal-immune circuit that generates a tumour-permissive niche before malignant outgrowth. Disruption of the amphiregulin-EGFR axis prevents early niche formation and abrogates tumour initiation. Conservation of this programme in KRASG12D-inducible human alveolar organoids and early-stage lung adenocarcinoma tissues identifies epithelial-microenvironment communication as a therapeutically actionable vulnerability and suggests that intercepting niche formation may prevent progression to treatment-resistant disease.
    DOI:  https://doi.org/10.1038/s41586-026-10399-6
  5. Nat Cancer. 2026 Apr 20.
    Heterogeneity and plasticity of cancer-associated fibroblasts.
    Sneha Pramod, Hagar Lavon, Ruth Scherz-Shouval, Mara H Sherman.
      Fibroblasts sense and respond to contextual cues to support tissue structure and function. In cancer, they engage a dysregulated wound-healing response that profoundly shapes tumor composition and progression. Efforts to therapeutically target these cancer-associated fibroblasts (CAFs) have been complicated by their heterogeneity and plasticity. However, recent advances, particularly in single-cell and spatial technologies, have greatly improved the understanding of the phenotypic consequences of distinct CAF states and functions. Here we review the current understanding of CAFs as heterogeneous, instructive regulators of tumor microenvironments across anatomic sites and highlight key challenges for the future.
    DOI:  https://doi.org/10.1038/s43018-026-01146-x
  6. Cell Death Dis. 2026 Apr 18.
    Decoding the CAF-TAM axis: multi-omics dissection and therapeutic targeting of stromal-immune crosstalk in the tumor microenvironment.
    Yage Fu, Mei Li, Shiwang Wu, Jingsi Wang, Shan Wang.
      Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are pivotal stromal and immune components of the tumor microenvironment (TME) that orchestrate immune evasion, metabolic reprogramming, and therapeutic resistance. Regions enriched in CAFs are frequently accompanied by dense TAM infiltration, underscoring their close structural and functional interdependence. Recent advances in single-cell, multi-omics, and spatial profiling technologies have revolutionized our understanding of the spatiotemporal heterogeneity, lineage evolution, and bidirectional signaling between CAFs and TAMs. In this review, we summarize the latest progress from transcriptomic, epigenomic, metabolomic, and spatial multi-omics studies, highlighting the diverse CAF/TAM subpopulations, their intercellular communication networks, and their collective roles in extracellular matrix remodeling, immune suppression, metabolic adaptation, and angiogenesis. Finally, we discuss emerging therapeutic strategies targeting CAFs, TAMs, and their interactive pathways, offering new conceptual and translational insights into reprogramming the immunosuppressive TME and enhancing antitumor efficacy.
    DOI:  https://doi.org/10.1038/s41419-026-08685-2
  7. Nat Rev Genet. 2026 Apr 22.
    TimeVault: a synthetic time capsule for transcriptome storage.
    Yu-Kai Chao.
      
    DOI:  https://doi.org/10.1038/s41576-026-00956-0
  8. Curr Opin Cell Biol. 2026 Apr 17. pii: S0955-0674(26)00031-1. [Epub ahead of print]100 102643
    Cancer signaling beyond the genes.
    Andre Levchenko, Ralitsa R Madsen.
      Cancer is still largely interpreted through the lens of genetic mutations, which continues to shape most therapeutic strategies. Yet single cell analyses reveal limits to this view: phenotypic heterogeneity is pervasive even among genetically identical cancer cells, and many canonical driver mutations are also present in non-malignant tissues. These paradoxes can be reconciled by viewing cancer as a new tissue state characterized by aberrant cellular information processing, where mutations act as context-dependent modifiers of the signaling codes. We advance a framework in which input-specific signaling dynamics determine phenotypic outcomes, while oncogenic mutations bias and blur these dynamics rather than acting as simple "on-off" switches. In this view, therapeutic success depends on restoring the fidelity of dynamic signal encoding and decoding rather than merely inhibiting isolated pathway components.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102643
  9. Nat Rev Cancer. 2026 Apr 24.
    The sleeping threat: targeting cancer dormancy to transform metastasis therapy.
    Julio A Aguirre-Ghiso, Jose Javier Bravo-Cordero, Wenjun Guo, Gregoire Lauvau, Maria Soledad Sosa.
      Metastatic cancer cell dormancy, wherein disseminated cancer cells (DCCs) persist in a quiescent state before reactivating to fuel metastasis, has emerged as a critical determinant of cancer relapse. In this Review, we synthesize recent advances in understanding the microenvironmental drivers of dormancy, including the role of niche-derived signals and extracellular matrix composition in maintaining DCC quiescence, as well as the epigenetic and transcriptional programmes, and chromatin remodelling that enforce and sustain dormancy. We also cover the mechanisms by which dormant DCCs evade immune surveillance, highlighting both innate and adaptive immune interactions, and the strategies tumours use to escape immune-mediated clearance. Although most data come from solid cancers, we also examine the biology of residual cells in haematologic malignancies that share key dormancy and relapse mechanisms with solid tumours. We also discuss how, despite these mechanistic insights, clinical translation remains limited, as available biomarkers or therapies targeting dormancy have yet to be effectively implemented. We conclude that by outlining the challenges and opportunities for leveraging dormancy biology, we may be able to prevent metastatic recurrence and improve patient outcomes.
    DOI:  https://doi.org/10.1038/s41568-026-00928-w
  10. Curr Opin Genet Dev. 2026 Apr 20. pii: S0959-437X(26)00040-7. [Epub ahead of print]98 102473
    Network analysis to understand gene regulation: across spatial scales and toward multi-level models.
    Vera Pancaldi.
      Current applications of network theory to biology have generally included two types of networks: spatially embedded ones, such as chromatin networks or tissue networks, and abstract representations of interactions, such as protein interactomes or interactions between drugs and their targets. We review recent network theory approaches to epigenomics and argue that expanding the formalisms that we use will be necessary to create more realistic, integrated models that better represent our understanding of complex biological entities and processes, such as gene regulation. On one hand, we need to view intracellular chromatin networks in the context of tissues to improve models of cell interactions. On the other hand, we need to move beyond transcriptional regulation and toward multiomics. We provide several examples of how network formalisms can support this endeavor, especially through applications in cancer research.
    DOI:  https://doi.org/10.1016/j.gde.2026.102473
  11. Neoplasia. 2026 Apr 21. pii: S1476-5586(26)00039-4. [Epub ahead of print]77 101310
    From inflammation to malignancy: the dynamic evolution of cancer-associated fibroblasts in IBD-CRC.
    Nobuhiro Naito, Hiroaki Kasashima, Tatsunari Fukuoka, Yuki Nakanishi, Naoko Ohtani, Kiyoshi Maeda.
      Inflammatory bowel disease-associated colorectal cancer (IBD-CRC) represents a distinct clinical and molecular entity characterized by long-standing inflammation and a unique "dysplasia-carcinoma" sequence. While epithelial genetic alterations are well-documented, the role of the mesenchymal stroma as a dynamic driver of malignant transformation remains underappreciated. In this review, we propose a conceptual framework where intestinal fibroblasts contribute significantly to niche construction as key components of the Tumor Microenvironment (TME) architecture. These cells are not merely passive scaffolds but dynamically co-evolve with the epithelium and immune compartment, transitioning into active orchestrators of the pre-malignant niche. We highlight the emerging concept of "stromal inflammatory memory," which is hypothesized to be encoded through stable epigenetic imprinting and persistent metabolic reprogramming, characterized by a PFKFB3-mediated glycolytic shift. This metabolic priming sustains a pro-tumorigenic environment even during clinical remission. We further delineate how the loss of apical polarity regulators, such as aPKC, triggers a cascade of epithelial-stromal crosstalk involving chronic microbial sensing and hyaluronan-driven signaling. This co-evolution leads to the diversification of cancer-associated fibroblast (CAF) subsets, including inflammatory (iCAF), myofibroblastic (myCAF), and antigen-presenting (apCAF) populations. These subsets collectively orchestrate immune evasion via T-cell exhaustion and physical immune exclusion. Finally, we discuss the clinical implications of the "Reverse Warburg Effect" and exosome-mediated chemoresistance. We emphasize that effective therapeutic strategies must transcend epithelial-centric models to target the stromal axis. By integrating recent advances in single-cell and spatial transcriptomics, we identify novel opportunities for "stromal reprogramming" through metabolic, epigenetic, and senomorphic interventions to prevent and treat IBD-CRC.
    Keywords:  Cancer-associated fibroblasts (CAFs); Epigenetic memory; IBD-CRC; Metabolic reprogramming; Therapeutic targeting; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.neo.2026.101310
  12. Nature. 2026 Apr 23.
    Wikipedia-based AI model reveals the 100 technologies to watch.
    James Mitchell Crow.
      
    Keywords:  Industry; Machine learning; Technology
    DOI:  https://doi.org/10.1038/d41586-026-00980-4
  13. Nature. 2026 Apr 22.
    Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.
    JRI Live Cell Bank
      Caspase 5 (CASP5) is a member of the inflammatory caspase family of cysteine proteases that is involved in inflammation and cell death1-3. CASP5 shares the highest homology with inflammatory CASP4, but whereas CASP4 is essential for noncanonical inflammasome activation, CASP5 is dispensable4-6, and its function remains unknown. Here we show that CASP5 is restricted to the human intestinal epithelium and manifests as three isoforms-CASP5A, CASP5B and CASP5C-among which CASP5C uniquely promotes Wnt signalling, which is essential for epithelial development and regeneration7. We identified dishevelled, which bridges Wnt receptors to the β-catenin destruction complex8, as a prominent CASP5 binding partner in colonic epithelial cells. Dishevelled interacts with the CASP5 catalytic domain through its DEP (dishevelled, EGL-10 and pleckstrin) domain. Lacking the inhibitory caspase activation and recruitment domain (CARD) of CASP5A and CASP5B, CASP5C cleaves the central scaffold protein APC at Asp556 in the Armadillo repeat domain, destabilizing the β-catenin destruction complex and thereby enhancing Wnt signalling. CASP5C expression peaks in transit-amplifying cells, the Wnt-reliant progeny of intestinal stem cells7, whereas CASP5A and CASP5B predominate in mature enterocytes. Endogenous and ectopic CASP5C drive growth of colonic and small intestinal organoids, which is known to require proliferation of transit-amplifying cells9. Furthermore, CASP5C is selectively induced upon intestinal epithelial injury, and its expression is increased in inflammatory bowel disease. Thus, CASP5C is an enzymatic amplifier of Wnt signalling that cleaves APC to sustain proliferation of transit-amplifying cells amid a declining Wnt gradient, safeguarding epithelial renewal. These findings broaden the roles of inflammatory caspases beyond innate immunity, uncovering their contribution to tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41586-026-10343-8
  14. Nat Commun. 2026 Apr 21.
    Microbiota-derived metabolites as modulators of cancer immunotherapy response.
    Catherine Toner-Bartelds, Iris L Mimpen, Miguel Parra-Martinez, Boudewijn M T Burgering, Emile E Voest.
      The microbiome is a key regulator of host homeostasis and immune activity, in part through the production of metabolites. These microbiota-derived metabolites can modulate both the innate and adaptive immune system, as well as directly target tumour cells, thereby regulating anti-tumour immunity and response to immunotherapy. Here, we describe the current mechanistic knowledge on how these metabolites exert their effects and outline the methodologies used to detect and assess these metabolites. Finally, we summarize microbiota-targeted therapies capable of improving microbial functionality to ultimately enhance immunotherapy responses and improve patient survival.
    DOI:  https://doi.org/10.1038/s41467-026-72178-1
  15. Annu Rev Biomed Data Sci. 2026 Apr 21.
    Beyond the Transcriptome: Leveraging Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) for Deeper Cellular Insights.
    Marina L Fernández, Felipe A Gajardo Escobar, Marcela K Sjöberg-Herrera, Pablo A Romagnoli, Danilo G Ceschin.
      The advent of single-cell genomics has revealed profound cellular heterogeneity, yet transcriptomic profiling alone often fails to show the functional proteomic state of a cell. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) emerged to bridge this critical gap, enabling the simultaneous quantification of RNA and surface protein expression within individual cells. This transformative technology leverages oligonucleotide-conjugated antibodies to assess protein abundance using a panel of marker-specific tags, which are cocaptured with cellular messenger RNA in single-cell sequencing workflows. This review details the methodological principles of CITE-seq, its compatibility with diverse sequencing platforms, and the computational frameworks required for integrated data analysis. We highlight its impact on cell biology, oncology, and infectious disease research, where it has refined cell classification, dissected tumor microenvironments, and decoded host-pathogen interactions. Finally, we discuss persistent technical and computational challenges and outline future directions, including spatial integration and predictive modeling, positioning CITE-seq as a cornerstone of next-generation biomedical discovery.
    DOI:  https://doi.org/10.1146/annurev-biodatasci-092724-061209
  16. Cancer Discov. 2026 Apr 20. OF1-OF20
    LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.
    Ray Pillai, Ali Rashidfarrokhi, Yuan Hao, Warren L Wu, Mariana C S Mancini, Burcu Karadal-Ferrena, Sofia G Dimitriadoy, Michael Cross, Anna H Yeaton, Shih Ming Huang, Arjun Bhutkar, Alberto M Herrera, Sahith Rajalingam, Makiko Hayashi, Kuan-Lin Huang, Eric Bartnicki, Anastasia-Maria Zavitsanou, Ellie Ivanova, Corrin Wohlhieter, Sarah E LeBoeuf, Ting Chen, Cynthia A Loomis, Ruth Kulicke, Fred P Davis, Nicolas Stransky, Gromoslaw Aleksander Smolen, Jun-Chieh J Tsay, Fernando Moreira Simabuco, Charles M Rudin, Andre L Moreira, Kamal M Khanna, Harvey I Pass, Kwok-Kin Wong, Shohei Koide, Aristotelis Tsirigos, Sergei B Koralov, Thales Papagiannakopoulos.
      LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression.
    SIGNIFICANCE: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0470
  17. Clin Chim Acta. 2026 Apr 18. pii: S0009-8981(26)00195-6. [Epub ahead of print] 121013
    Emerging biomarkers for early detection of colorectal cancer.
    Reem A Qannita, Ruba A Zenati, Ahmad Y Abuhelwa, Mohammad A Y Alqudah, Shereen M Aleidi, Waseem El-Huneidi, Eman Abu-Gharbieh, Zainab M AlShareef, Karem H Alzoubi, Yasser Bustanji, Mohammad H Semreen.
      The worldwide impact of colorectal cancer (CRC) as a primary cause of cancer-related morbidity and mortality demonstrates the urgent need for better early detection methods and personalized treatment approaches. While colonoscopy and fecal tests have contributed to reduced mortality rates from CRC, they encounter important limitations stemming from their invasive procedures and insufficient sensitivity plus patient adherence issues. Consequently, the latest progress in molecular biology and omics technologies has enabled researchers to identify new biomarkers which present effective solutions for early detection and risk assessment while monitoring treatment efficacy. Therefore, this review explores new developments in CRC biomarker research through the lens of emerging liquid biopsy methods like circulating tumor DNA (ctDNA) and microRNAs (miRNAs) as well as genomic, epigenomic, gut microbiome, metabolomic, and proteomic markers. The usage of biomarker-based methods demonstrates transformative potential for CRC treatment by boosting survival rates and lessening global impact through precision medicine development in oncology.
    Keywords:  Biomarkers; Colorectal cancer; Early detection; Epigenetics; Genomics; Liquid biopsy; Metabolomics; Microbiome; Precision medicine; Proteomics; ctDNA; miRNA
    DOI:  https://doi.org/10.1016/j.cca.2026.121013
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒27 at 10:59.