bims-gerecp 2026-08-30 papers

bims-gerecp

Biomed News

on Gene regulatory networks of epithelial cell plasticity

Issue of 2026–08–30
twenty-two papers selected by
Xiao Qin, University of Oxford

Shaping the future of early-onset colorectal cancer prevention.
Oncofetal cell states: cell plasticity drives invasion in premetastatic colorectal tumors.
Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.
Cancer Stem Cells in Colorectal Cancer: From Molecular Mechanisms to Diagnosis, Prognosis and Therapy Implications.
Mirror worlds: The shared regulatory architecture of cell fate in development and cancer.
Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer.
Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation.
Emerging exposure-driven accelerated colorectal carcinogenesis: a model with implications for screening colonoscopy effectiveness.
All-optical multimodal mapping of single-cell-type-specific metabolic activities via REDCAT.
A developmental biologist's guide to mechanics.
Data-centric feedback loops for next-generation immunotherapy development.
Spatiotemporal dynamics of intestinal immune cells.
iPSC models of hereditary cancer predisposition: Mechanistic insights into premalignant evolution and lineage-specific vulnerability.
Colorectal Cancer and the Enigma Surrounding Non-Canonical Wnt Signaling.
Induced pluripotent stem cells from discovery to translation.
A multimodal, all-optical platform for linking cell identity to metabolic function in intact tissues.
Mechanical memory in cells: mechanisms, effects, and applications in regenerative medicine.
Micrometastasis as a distinct immunobiological state and therapeutic target.
Microbiome signatures for detection of colorectal lesions in population-based FIT screening.
Multi-kingdom signatures of the gut microbiome in Lynch syndrome: a prospective model for colorectal cancer evolution.
scProtoTransformer: Scalable reference mapping across molecules, cells, and donors.
MicroRNAs and Other Small RNAs in Liquid Biopsies as Biomarkers for Early Detection of Colorectal Cancer.

Nat Rev Cancer. 2026 Aug 26.

Shaping the future of early-onset colorectal cancer prevention.

Ruiyi Tian, Sina Azadnajafabad, Erika A Waters, Emily P Balskus, Yasmine Belkaid, Jordana T Bell, Sarah E Berry, Jason D Buenrostro, Curtis Huttenhower, Anisha Patel, Gary J Patti, Nicola Segata, Bhawna Sirohi, Tim D Spector, Ömer H Yilmaz, Andrew T Chan, Yin Cao.

Early-onset colorectal cancer (EOCRC) among individuals under age 50 is increasing globally. Lifestyle factors such as obesity, metabolic comorbid conditions, poor diet and sedentary behaviours are linked to EOCRC, but critical gaps remain in identifying additional risk factors, with growing evidence for early-life and gut microbial-related exposures. In addition, how or when the risk factors act, individually or collectively, to initiate or promote colorectal cancer at much younger ages remains unknown. Compounding the complexity are the unique challenges of developing and implementing effective prevention strategies among younger populations. In this Roadmap, we review the progress and challenges of risk factor discovery for EOCRC, highlight opportunities for prevention and propose a transdisciplinary framework integrating population, mechanistic, behavioural and implementation sciences to accelerate causal risk factor discovery and translate insights into strategies to reverse the rising EOCRC burden. This framework, exemplified by emerging global initiatives including the Cancer Grand Challenges team PROSPECT, is broadly adaptable and intended to inspire collaborative efforts across the field. We also emphasize the critical role of patient perspectives and public engagement in shaping these efforts. With the urgency in risk factor discovery, scientists, the public and policymakers must unite to transform knowledge into life-saving solutions for future generations.

DOI: https://doi.org/10.1038/s41568-026-00965-5
Signal Transduct Target Ther. 2026 Aug 28. pii: 352. [Epub ahead of print]11(1):

Oncofetal cell states: cell plasticity drives invasion in premetastatic colorectal tumors.

Mahmoud N A Amer, Florian R Greten.

DOI: https://doi.org/10.1038/s41392-026-02941-9
Cell. 2026 Aug 28. pii: S0092-8674(26)00929-3. [Epub ahead of print]

Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.

Ronghui Zhu, Emma Dann, Jun Yan, Justine Reyes Retana, Ryunosuke Goto, Reese C Guitche, Lillian Brixi, Mineto Ota, Austin Hartman, Theodore L Roth, Ansuman T Satpathy, Jonathan K Pritchard, Alexander Marson.

  Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4+ T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allowed us to map genes regulating immune pathways, including previously uncharacterized regulators of cytokine production. Importantly, active regulators and the gene programs they control changed dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of T cell polarization and of age-related phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our study provides a foundational resource and new approaches to decode T cell function and human immune traits.

Keywords:  CD4(+) T cell polarization; CD4(+) T cells; CRISPR; CRISPR interference; CRISPRi; T cell aging; cell fate decision; functional genomics; gene regulatory networks; human T cells; human genetics; perturb-seq; perturbation signatures; primary human cells; probe-based perturb-seq

DOI:  https://doi.org/10.1016/j.cell.2026.08.002
Cancers (Basel). 2026 Aug 10. pii: 2569. [Epub ahead of print]18(16):

Cancer Stem Cells in Colorectal Cancer: From Molecular Mechanisms to Diagnosis, Prognosis and Therapy Implications.

Dami Aiyejuto, Ananya Luthria, Thompson Hui, Anitha Kota Shenoy.

  Colorectal cancer (CRC) remains a major cause of cancer-related mortality, with recurrence and treatment resistance as persistent challenges. Increasing evidence supports the cancer stem cell (CSC) model in CRC, in which a subpopulation of self-renewing colorectal cancer stem cells (CCSCs) sustains tumor growth, metastasis, and therapy resistance. CCSCs are increasingly recognized as key drivers of tumor progression, therapeutic resistance, and relapse, and are increasingly being investigated not only as therapeutic targets but also as biomarkers with diagnostic and prognostic relevance in CRC. Multiple signaling pathways regulate CCSC maintenance and aggressive behavior, including Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT, MAPK/ERK, NF-κB, and TGF-β signaling. These pathways form the basis of therapeutic strategies aimed at modulating stemness-associated pathways, with several CSC-focused agents and pathway inhibitors currently under translational and clinical investigation. In parallel, CCSC surface markers and molecular signatures are being explored as putative tools for early detection, minimal residual disease monitoring, and outcome prediction. However, successful translation of CSC-directed approaches into effective and safe clinical applications remains difficult. Tumor heterogeneity, CSC plasticity, compensatory signaling mechanisms, and the shared regulatory networks between malignant and normal intestinal stem cells pose substantial barriers. In this review, we summarize the molecular mechanisms underlying CCSC biology, discuss their diagnostic and prognostic implications. We also focus on clinical trials that apply CCSC-directed therapeutic, biomarker, and prevention strategies in CRC., Finally, we emphasize the lessons learned and the translational challenges, including the need for rigorously validated, CCSC-specific biomarkers, that continue to shape the development of these therapeutic and biomarker strategies.

Keywords:  cancer stem cells (CSC); clinical trials; colorectal cancer (CRC); colorectal cancer stem cells (CCSC); diagnostic biomarkers; drug resistance; metastasis; prognostic biomarkers; signaling pathways; therapeutic resistance; therapeutic targeting; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers18162569
Cancer Lett. 2026 Aug 25. pii: S0304-3835(26)00563-X. [Epub ahead of print]659 218799

Mirror worlds: The shared regulatory architecture of cell fate in development and cancer.

Melanie Fraidenburg, Longjun Li, Rosa Kwon, Fady Ghali, Joshua Warrick, Michael S Leapman, Isaac Yi Kim, Ping Mu.

Lineage plasticity has emerged as a central mechanism through which cancer cells adapt to therapeutic pressure, evade immune surveillance, and acquire aggressive phenotypes. Although recognized across tumor types, the regulatory principles governing how cancer cells reprogram cellular identity remain incompletely understood. In this review, we propose that lineage plasticity in cancer reflects the redeployment of regulatory frameworks established during normal development. Rather than representing a stochastic byproduct of genomic instability, cancer plasticity frequently unfolds within gene regulatory architectures that also govern cell fate specification, lineage commitment, and controlled state transitions during embryogenesis and tissue homeostasis. Developmental transcription factors, including members of the SOX family, FOXA1, ASCL1, NKX2-1, and epithelial-mesenchymal transition regulators, function as lineage gatekeepers during development but are repurposed in cancer to destabilize lineage commitment and enable phenotypic switching. Similarly, epigenetic regulators that guide developmental trajectories, including chromatin remodeling complexes, Polycomb group proteins, and DNA methylation machinery, are frequently dysregulated or redistributed in tumors, altering the repression of lineage-stabilizing and alternative lineage programs and thereby weakening epigenetic barriers to lineage transitions. Together, these observations support a model in which development and cancer operate as mirror regulatory systems: one establishing and stabilizing cellular identity, the other exploiting the same regulatory architecture to permit adaptive reprogramming under selective pressure. We further discuss how emerging single-cell and spatial multi-omics technologies, integrated with artificial intelligence-based modeling, enable mapping of cell state landscapes and transitional trajectories, transforming lineage plasticity from a descriptive phenomenon into a measurable and predictable property of tumor evolution.

DOI: https://doi.org/10.1016/j.canlet.2026.218799
Nat Genet. 2026 Aug 26.

Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer.

Pasquale Laise, Mikko Turunen, Alvaro Curiel-Garcia, Lorenzo Tomassoni, H Carlo Maurer, Ela Elyada, Bernhard Schmierer, Jeremy Worley, Jordan Kesner, Xiangtian Tan, Ester Calvo Fernandez, Yuanqing Xue, Yining Chen, Kelly Wong, Urszula N Wasko, Somnath Tagore, Alexander L E Wang, Sabrina Ge, Alina C Iuga, Aaron T Griffin, Winston Wong, Gulam A Manji, Mariano J Alvarez, Faiyaz Notta, David A Tuveson, Kenneth P Olive, Andrea Califano.

There is broad consensus that the malignant epithelial cells of human pancreatic ductal adenocarcinoma (PDA) comprise multiple, molecularly distinct states. Yet precise characterization of how these are regulated-including their mechanistic determinants, dependencies, plasticity and functional properties-remains elusive. Single-cell master regulator (MR) analysis of multiple PDA cohorts identified malignant cells in three co-existing, molecularly distinct developmental lineage states, with distinct histopathological morphologies and spatial architecture. These include a poorly differentiated lineage driven by epithelial-mesenchymal-transition-related MRs and two well-differentiated states driven by gastrointestinal epithelial development and pancreatic development MRs, respectively. Furthermore, each state comprises two epigenetically distinct substates with low versus high MAPK signaling activity. Barcode-based lineage tracing confirmed both spontaneous and treatment-dependent cross-state plasticity. Furthermore, loss-of-function studies confirmed state-specific MR essentiality, while their ectopic expression effectively reprogrammed cell state, in vitro and in vivo, thus providing a mechanism-based foundation for PDA heterogeneity and a roadmap for pharmacological targeting.

DOI: https://doi.org/10.1038/s41588-026-02714-8
Immunity. 2026 Aug 26. pii: S1074-7613(26)00321-3. [Epub ahead of print]

Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation.

Idan Adir, Carmel Sochen, Sivan Gelb, Aviya Habshush Menachem, Sacha Lebon, Barak Toval, Vladyslav Holiar, Natalia Davidzohn, Tomer-Meir Salame, Irit Rosenhek-Goldian, Simonas Savickas, Fabio Sabino, Valerio Izzi, Bella Ungar, Alon Abend, Inna Solomonov, Ehud Zigmond, Taina Pihlajaniemi, Ulrich Auf dem Keller, Moshe Biton, Irit Sagi.

  Tissue regeneration is viewed as a return to homeostasis, but whether the extracellular matrix (ECM) reverts during recovery from gut inflammation is unclear. Using temporal multi-omics, biomechanical profiling, and spatial fate mapping in colitis models, we showed that colonic ECM underwent lasting pathological reprogramming following inflammation, which we termed modified (mod)ECM. Characterized by collagen XVIII accumulation and immune-driven proteolysis, modECM redirected intestinal stem cells (ISCs) toward a wound-associated epithelial state with a pro-inflammatory transcriptional program. Ex vivo, modECM alone reshaped ISC fate by suppressing Wnt signaling and activating immune recruitment pathways. In vivo, modECM-rich zones sustained T cell infiltration and KRT14+ epithelial cell emergence from Lgr5+ progenitors. This aberrant epithelial program was mirrored in inflamed rectal biopsies from individuals with ulcerative colitis. Our findings redefine the ECM as a long-lived instructive compartment that encodes injury memory and promotes maladaptive regeneration, positioning it as a therapeutic target in chronic inflammatory diseases.

Keywords:  ECM; ECM remodeling; ISC; T cell recruitment; collagen XVIII; colon; extracellular matrix; intestinal stem cell; pathological reprogramming; tissue regeneration; wound-associated epithelia

DOI:  https://doi.org/10.1016/j.immuni.2026.07.022
Gut. 2026 Aug 24. pii: gutjnl-2026-339128. [Epub ahead of print]

Emerging exposure-driven accelerated colorectal carcinogenesis: a model with implications for screening colonoscopy effectiveness.

Kaspar Truninger, Hariharan Easwaran, Finlay Macrae, Primo Schär, Hassan Fazilaty.

  Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide, with its burden projected to rise. Screening average-risk individuals is recommended because several strategies reduced CRC incidence and mortality. While overall CRC incidence and mortality have stabilised or declined in many developed regions, rates increase in low- and middle-income countries, alongside a global surge in early-onset CRC (EOCRC). The previous shift toward earlier-stage diagnosis has reversed, with rising distal and rectal tumours, despite these being more amenable to prevention by screening. Even when performed with highest quality, guideline-concordant screening and surveillance cannot fully prevent CRC and post-colonoscopy CRC (PCCRC). These patterns suggest that current slowly progressing precursor-based models of tumourigenesis may not fully explain all emerging CRC phenotypes. We propose that sporadic microsatellite-stable EOCRC and a subset of PCCRC represent sentinel manifestations of a broader, under-recognised process of exposure-related accelerated carcinogenesis. In this conceptual model, environmental and lifestyle exposures may promote subclinical inflammation, immune dysregulation, microbiome disruption and epigenetic remodelling, thereby compressing the timeline from early mutational events to overt tumourigenesis. We postulate that cumulative exposures converge to create biologically permissive tissue states that enable accelerated malignant transition, either through shortened, subtle precursor phases or directly from dysplastic mucosa. We introduce oncoembryonic reprogramming as a potential molecular mechanism linking exposure-driven mucosal remodelling to accelerated tumour progression and malignant competence. This proposed model may help explain why some CRCs are not prevented by conventional precursor-based strategies and could have relevant implications for risk stratification, screening strategies and translational targeting.

Keywords:  COLORECTAL CANCER

DOI:  https://doi.org/10.1136/gutjnl-2026-339128
Nat Methods. 2026 Aug 27.

All-optical multimodal mapping of single-cell-type-specific metabolic activities via REDCAT.

Yajuan Li, Zhaojun Zhang, Archibald Enninful, Negin Farzad, Presha Rajbhandari, Hua Tian, Jungmin Nam, Xiaoyu Qin, Jorge Villazon, Anthony A Fung, Hongje Jang, Zhiliang Bai, Nancy R Zhang, Brent R Stockwell, Rong Fan, Mina L Xu, Zongming Ma, Lingyan Shi.

Metabolism is fundamental to cell function, yet its activities vary across tissue environments. Resolving these processes in situ at single-cell resolution is crucial for understanding physiology in health and disease. However, existing methods lack biochemical specificity or direct linkage to cell identity. Here we report a method, Raman Enhanced Delineation of Cell Atlases in Tissues (REDCAT), an all-optical platform integrating Raman scattering microscopy and high-plex immunofluorescence to co-map metabolism and cell types. REDCAT achieves subcellular profiling of protein, lipid, nuclear metabolites and redox metabolism in human tissues. In lymph nodes, it revealed cell-type-specific metabolic specialization. In lymphoma, REDCAT uncovered profound reprogramming and transitional states during tumor transformation. In the liver, it resolved zonation-dependent metabolic gradients. By linking cell identity to spatial metabolic states, REDCAT provides a framework for studying immunity and cancer, offering a path to deciphering the metabolic basis of disease.

DOI: https://doi.org/10.1038/s41592-026-03180-0
Development. 2026 Aug 15. pii: dev205785. [Epub ahead of print]153(16):

A developmental biologist's guide to mechanics.

Jialing Cao, Alessandro Chiappori, Sylvain Landiech, Raphaël Clément, Pierre-François Lenne.

  Developmental biology seeks to explain how living systems self-organize into functional, robust forms. While molecular and genetic approaches have revealed how biological information is encoded and processed, they often do not explain how this information is translated into physical shape. Here, we introduce the mechanical principles underlying tissue morphogenesis, aimed at developmental biologists with little background in physics. This Primer is structured around three core pillars. First, force generation describes how active and passive processes within cells and tissues drive deformation and motion. Second, constitutive behavior defines how living matter responds to these forces, spanning elastic, viscous and plastic regimes. Third, geometry and boundary constraints set the spatial constraints that shape mechanical interactions at the tissue and organismal levels. Together, these elements provide a framework for understanding how form emerges from the interplay between forces, material properties and geometry. We illustrate key examples across developmental processes and highlight recent advances and future challenges, integrating mechanical and molecular perspectives to guide the study of morphogenesis.

Keywords:  Boundary constraints; Constitutive behavior; Force generation; Physics of morphogenesis; Shapes

DOI:  https://doi.org/10.1242/dev.205785
Nat Biomed Eng. 2026 Aug 28.

Data-centric feedback loops for next-generation immunotherapy development.

Rotem Shalita, Ido Amit.

Despite explosive growth in biomedical data generation, driven largely by genomics, and in computational capabilities, the probability that a candidate entering phase I ultimately reaches approval has remained stubbornly low over the past decades. This paradox points to a central bottleneck not in data generation, but in converting biological and clinical data into decisions that govern progression, redesign or termination. Here we argue that drug development should be reframed from a linear pipeline into an iterative learning system driven by continuous data feedback. We outline a data-centric framework in which high-dimensional, multimodal molecular and perturbation data, particularly single-cell and spatial readouts, are used to iteratively refine disease models, therapeutic hypotheses, molecular designs and patient stratification strategies across discovery and clinical stages. Using immunotherapies as a proof-of-concept domain, we propose that single-cell molecular readouts from therapeutic perturbations can both de-risk development and deepen mechanistic understanding of immune responses in humans. Finally, we draw parallels to reinforcement learning, in which human molecular and clinical data provide the feedback signal that updates mechanistic models and guides the design of subsequent interventions. Embracing this paradigm offers a path towards more mechanistically grounded, context-aware therapies with higher translational success.

DOI: https://doi.org/10.1038/s41551-026-01785-6
Curr Opin Immunol. 2026 Aug 27. pii: S0952-7915(26)00113-5. [Epub ahead of print]102 102836

Spatiotemporal dynamics of intestinal immune cells.

Michela Frascoli, Silvia Galván Peña.

Intestinal immunity is coordinated by the spatial organization and temporal regulation of immune cells within a complex, antigen-rich environment. In this review, we discuss the latest advances in our understanding of how these two fundamental dimensions together shape intestinal immune homeostasis. We first examine the temporal dynamics of intestinal immunity, ranging from prenatal immune development, early-life immune education, and differentiation established by maternal factors and dietary changes. We discuss recent discoveries identifying RORγt-expressing antigen-presenting cells as key regulators of oral tolerance, providing a mechanism for how transient developmental windows establish long-lasting immune homeostasis. We then explore the spatial organization of intestinal immune cells, from regional specialization along the length of the gastrointestinal tract to compartment-specific immune populations, as well as micro-niches revealed by emerging spatial technologies. We review specialized chemokine networks, cellular interactions, and the microenvironments that coordinate immune responses in distinct intestinal regions. As we face increasingly detailed spatiotemporal maps, the next challenge will be to translate all this information into mechanisms underpinning how immune niches are established and maintained to promote intestinal health.

DOI: https://doi.org/10.1016/j.coi.2026.102836
Biochim Biophys Acta Rev Cancer. 2026 Aug 26. pii: S0304-419X(26)00167-8. [Epub ahead of print]1881(5): 189695

iPSC models of hereditary cancer predisposition: Mechanistic insights into premalignant evolution and lineage-specific vulnerability.

Bei-Bei Gan, Qing-Bo Yang, Wen-Liang Li, Ning Xu.

  Hereditary cancer carrier tissues are difficult to sample before transformation, limiting direct study of early disease evolution. Induced pluripotent stem cells (iPSCs) preserve inherited genetic context and enable controlled reconstruction of susceptible lineages and defined second hits. Across hereditary breast and ovarian cancer, mismatch repair deficiency, Li-Fraumeni syndrome and familial adenomatous polyposis, current evidence is strongest but uneven for BRCA1/2/PALB2-, MMR-, TP53- and APC-associated models. Collectively, these systems show that lineage state, contextual stress and acquired second hits shape DNA-repair defects, clonal selection and premalignant evolution. However, developmental immaturity, incomplete stromal and immune context, clonal drift and protocol variability constrain interpretation. iPSC models should therefore be used as mechanistic filters for testing causality, comparing lineage vulnerability and prioritising biomarkers or prevention hypotheses, rather than as stand-alone predictors of individual cancer risk or clinical outcome. Their outputs require validation in adult tissues, patient-derived models and carrier cohorts.

Keywords:  Functional variant interpretation; Hereditary cancer predisposition syndromes; Induced pluripotent stem cells; Lineage-specific vulnerability; Premalignant evolution; Second-hit biology

DOI:  https://doi.org/10.1016/j.bbcan.2026.189695
Cancers (Basel). 2026 Aug 14. pii: 2618. [Epub ahead of print]18(16):

Colorectal Cancer and the Enigma Surrounding Non-Canonical Wnt Signaling.

Katsuhiro Kita.

  Since the discovery of truncated mutations of adenomatous polyposis coli proteins in familial adenoma patients in 1991, the mechanism of cytosolic β-catenin regulation has been intensively studied, and now it is very well known that the central role of the canonical Wnt/β-catenin is in colorectal cancer. However, Wnt signaling is very complicated because of the presence of almost 20 Wnt ligand genes, six Frizzled seven-transmembrane receptors, and three LRP co-receptors. In addition, research in the past two decades illuminated the existence of the other Wnt signaling-non-canonical Wnt signaling (Wnt/PCP and Wnt/Ca2+ pathways), and an increasing number of studies have shown the potential role of non-canonical Wnt signaling in cancer recently. One of the well-studied Wnt ligands in non-canonical Wnt signaling is Wnt-5a. However, the role of Wnt-5a and non-canonical pathways in cancer is mosaic-i.e., it may involve tumor-promoting or suppressing pathways. In certain cancers, non-canonical Wnt signaling may mainly act as a tumor promoter, yet the results are very controversial in colorectal cancer. Elucidating the role of non-canonical Wnt signaling in colorectal cancer may be very important to further reduce the risk of colorectal cancer, especially in patients who do not carry truncated mutations of adenomatous polyposis coli. In this review, I would like to mainly discuss the apparent controversy surrounding non-canonical Wnt signaling in colorectal cancer, and I would like to point out a few potential reasons contributing to the mysterious roles of Wnt5a-initiated non-canonical signaling in colorectal cancer.

Keywords:  ROR2; Wnt-5a; cancer-associated fibroblasts; colorectal cancer; hypoxia; non-canonical Wnt

DOI:  https://doi.org/10.3390/cancers18162618
Nat Med. 2026 Aug 27.

Induced pluripotent stem cells from discovery to translation.

Jaecheol Lee, Todd Herron, Lorenz Studer, Christine L Mummery, Joseph C Wu.

Two decades after the introduction of induced pluripotent stem cell (iPSC) technology, the field has evolved from a seminal biological discovery into a transformative clinical platform. This maturation reflects a convergence of nonintegrating cellular reprogramming, efficient differentiation protocols, high-fidelity tissue engineering and precise genome editing-which together have established a platform-level framework for recapitulating and probing human disease biology in human cell-based systems. While these milestones have enabled the first wave of iPSC-based therapeutic clinical trials and recent early approvals, the transition to standardized, widely deployable therapies remains constrained by inherent biological variability, manufacturing complexities and the need for long-term safety surveillance. This Review evaluates the technological and translational trajectories that have defined the iPSC era and analyzes the operational barriers to therapeutic development. Looking forward, we discuss how integrating automation and artificial intelligence could redefine iPSC workflows as scalable systems. We present a roadmap for the next 20 years, envisioning a paradigm shift in which iPSC-derived interventions transition from bespoke experimental models toward standardized, engineered biological medicines.

DOI: https://doi.org/10.1038/s41591-026-04584-3
Nat Methods. 2026 Aug 27.

A multimodal, all-optical platform for linking cell identity to metabolic function in intact tissues.

DOI: https://doi.org/10.1038/s41592-026-03181-z
Front Bioeng Biotechnol. 2026 ;14 1922947

Mechanical memory in cells: mechanisms, effects, and applications in regenerative medicine.

Antara Bhuyan, Mark Ahearne.

  Mechanical memory is the ability of cells to retain information from past mechanical environments, which profoundly influences cellular behaviour and fate, particularly in stem cells. This review combines contemporary insights into mechanical memory with specific attention to its underlying processes, which span mechanotransduction to epigenetic alterations. Various approaches to study mechanical memory have been investigated through substrate stiffness modulation, shear stress, and cyclic strain while evaluating the impact of mechanical memory on several cell types. Applications in regenerative medicine are discussed, including stem cell expansion, tissue engineering, and disease treatment. Future research directions are proposed to enhance the understanding and control of mechanical memory for therapeutic advancements, addressing gaps in molecular mechanisms and clinical translation.

Keywords:  biomaterials; mechanical memory; mechanobiology; mechanotransduction; stem cells; substrate stiffness

DOI:  https://doi.org/10.3389/fbioe.2026.1922947
Trends Immunol. 2026 Aug 28. pii: S1471-4906(26)00189-4. [Epub ahead of print]

Micrometastasis as a distinct immunobiological state and therapeutic target.

Silvia Avalle, Toni Celià-Terrassa.

  Metastasis is an inefficient cellular process in which most disseminated tumor cells fail to form secondary lesions in distant tissues due to hostile conditions, such as protective immune surveillance. The few cells that survive these threats can seed subclinical metastatic lesions, known as micrometastases, which are the least-known stage of the metastatic cascade. In this study, we review micrometastasis immunobiology, which differs from that of larger, clinically manifested metastasis. Key mechanisms such as epithelial-to-mesenchymal transition, stemness, dormancy, and immune evasion shape this bottleneck of metastasis, determining long-term disease evolution, therapy responses, and patient outcomes. Understanding micrometastasis immunology may reveal therapeutic opportunities to fully eradicate disseminated cells. Thus, we discuss emerging time-tailored immunopreventive strategies to intercept the progression to overt metastasis.

Keywords:  MRD; immune evasion; immunoediting; immunotherapy; metastasis; micrometastasis

DOI:  https://doi.org/10.1016/j.it.2026.07.010
Nat Commun. 2026 Jul 23. pii: 8982. [Epub ahead of print]17(1):

Microbiome signatures for detection of colorectal lesions in population-based FIT screening.

Einar E Birkeland, Ane S Kværner, Ekaterina Avershina, Cecilie Bucher-Johannessen, Vahid Bemanian, Hege S Blix, Anette Hjartåker, Willem M de Vos, Giske Ursin, Geir Hoff, Kristin R Randel, Edoardo Botteri, Paula Berstad, Trine B Rounge.

The gut microbiome has been linked to colorectal cancer (CRC) development, with microbe-based classifiers distinguishing between CRC patients and healthy controls. However, there is a lack of studies addressing the utility of the microbiome in screening-relevant settings, including both precancers and CRC. In this Norwegian population-based study, we used fecal immunochemical test (FIT) leftovers from 1034 FIT-positive (i.e. positive for occult blood) screening participants for gut metagenome profiling using shotgun sequencing. Using comprehensive clinical, demographic, and lifestyle data, we modeled gut microbiome associations with CRC screening outcomes. Combining microbial profiles with quantitative FIT values improved detection of premalignant lesions beyond optimizing the FIT value alone, even after incorporating established CRC risk factors. Still, the FIT value maintained superior discriminative ability for CRC. We confirmed enrichment of bacteria such as Fusobacterium nucleatum and Peptostreptococcus stomatis in CRC. In contrast, other bacteria previously associated with the presence of CRC, including Hungatella hathewayi and Clostridium symbiosum, as well as pks-negative Escherichia coli, were enriched in those with no neoplastic findings, suggesting that in a FIT-positive population their presence may reflect other conditions causing intestinal bleeding rather than underlying neoplasia. Microbial profiles were predominantly associated with distal rather than proximal lesions. Together, our findings highlight the potential for microbial markers to improve FIT-based CRC screening, especially by differentiating those with premalignant lesions from those who test FIT-positive for other reasons.

DOI: https://doi.org/10.1038/s41467-026-75962-1
Gut. 2026 Aug 25. pii: gutjnl-2026-339088. [Epub ahead of print]

Multi-kingdom signatures of the gut microbiome in Lynch syndrome: a prospective model for colorectal cancer evolution.

Nanako Shirai, Amrisha Bhosle, Etienne Nzabarushimana, Jiaxian Shen, Yan Yan, Hanseul Kim, Chahat Upreti, Prooksa Ananchuensook, Elena Stoffel, Sonia S Kupfer, Daniel C Chung, Kelsey N Thompson, David A Drew, Zsofia K Stadler, Curtis Huttenhower, Andrew T Chan, Long H Nguyen.



Keywords:  COLORECTAL CANCER; METAGENOMICS; MICROBIOME

DOI:  https://doi.org/10.1136/gutjnl-2026-339088
Sci Adv. 2026 Aug 28. 12(35): eaef0286

scProtoTransformer: Scalable reference mapping across molecules, cells, and donors.

Zhenchao Tang, Haohuai He, Shouzhi Chen, Jun Zhu, Tianxu Lv, Jiale Zhou, Jiehui Huang, Yaokun Li, Guanxing Chen, Linlin You, Calvin Yu-Chian Chen.

The rapid accumulation of single-cell data has made it possible to comprehensively characterize biological systems at molecular, cellular, and donor levels. However, scalable reference mapping across different resolutions remains a major challenge in current research. Here, we propose scProtoTransformer, a prototype-based Transformer architecture designed to achieve scalable reference mapping across molecular, cell, and donor levels. scProtoTransformer introduces a knowledge-guided prototype tokenizer that projects gene expression into biologically interpretable pathway prototypes, effectively reducing numerical batch effects while preserving biological semantic patterns. Furthermore, by leveraging knowledge distilled from the foundation model and a dynamic supervised fine-tuning strategy, scProtoTransformer achieves robust biological representations with reduced pretraining requirements. Benchmark experiments across molecular, cell, and donor-level reference mapping demonstrate that scProtoTransformer delivers competitive or even superior performance compared with state-of-the-art approaches while providing interpretability through biological prototypes. Together, these results establish scProtoTransformer as a unified framework for scalable reference mapping, laying the foundation for systematic understanding from genes to individuals.

DOI: https://doi.org/10.1126/sciadv.aef0286
Int J Mol Sci. 2026 Aug 07. pii: 7095. [Epub ahead of print]27(16):

MicroRNAs and Other Small RNAs in Liquid Biopsies as Biomarkers for Early Detection of Colorectal Cancer.

Natalia Navarro, Javier Gómez-Matas, Carla Di Battista, Meritxell Gironella.

  Early detection of colorectal cancer (CRC) is a major determinant of patient prognosis, as survival strongly depends on disease stage at diagnosis. Despite advances in screening programs, a significant proportion of CRC cases are still diagnosed at advanced stages, underscoring the need for improved early detection strategies. Most sporadic CRCs arise through the adenoma-carcinoma sequence over 10 to 15 years, providing a window for the detection of premalignant lesions, such as advanced adenomas. Current screening approaches are based on colonoscopy or its combination with stool-based tests. Although colonoscopy is the gold standard, it is an invasive technique with high associated costs and limited patient compliance. Stool-based tests are non-invasive and more widely accepted but lack specificity and sufficient sensitivity for detecting premalignant lesions. In this context, liquid biopsies have emerged as a promising minimally invasive alternative for identifying tumor-derived biomarkers in biological fluids such as blood or stool. Small non-coding RNAs (sncRNAs), and particularly microRNAs (miRNAs), have gained considerable attention as non-invasive biomarkers for their highly stability, resistance to handling conditions, and reliable quantification even in low-input samples. Single miRNAs and miRNA signatures detected in biofluids and combined with clinical parameters have shown promise for CRC detection. However, their utility for detecting advanced adenomas remains insufficiently characterized. Further validation in large, independent cohorts and standardization of analytical methods are required before their clinical implementation. Despite these challenges, sncRNA-based liquid biopsies represent a promising approach for improving early detection of CRC and, consequently, its prognosis.

Keywords:  CRC screening; advanced adenoma; colorectal cancer; liquid biopsy; miRNA

DOI:  https://doi.org/10.3390/ijms27167095