bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–03–15
24 papers selected by
Xiao Qin, University of Oxford
  1. stVCR: spatiotemporal dynamics of single cells.
  2. Gene regulatory networks: from correlative models to causal explanations.
  3. Comparison of large language models and expert multidisciplinary team decisions in colorectal cancer.
  4. Gut microbiome in colorectal cancer: recent advances and clinical implications.
  5. Research advances in early screening for colorectal cancer (Review).
  6. Immune Niches in Cancer.
  7. Whole-embryo spatial transcriptomics at subcellular resolution from gastrulation to organogenesis.
  8. PI3K and MAPK Signaling Nodes Serve as Divergent Drivers of Phenotypic Plasticity in Cancer-Associated Fibroblasts in Colorectal Cancer.
  9. Stochastic modeling of epigenetic memory.
  10. Organoids revolutionizing precancer research.
  11. An update on spatial proteomics.
  12. Pericytes and mesenchymal stromal cells converge toward pro-tumor phenotypes in the tumor microenvironment.
  13. How will we know if AI is smart enough to do science?
  14. Genetic recording and in situ readout of single-cell signaling memory.
  15. Cancer interception with KRAS inhibitors in preclinical models of pancreatic ductal adenocarcinoma.
  16. Targeting metabolism to combat anticancer and antibacterial drug resistance.
  17. Advancements in organoid models emulating metastatic niches.
  18. Next-generation programmable cell therapies for precision medicine.
  19. Toward a consensus on the tumor microbiota: Evidence, standards, and interpretation.
  20. Ageing promotes metastasis via activation of the integrated stress response.
  21. Circulating Tumor DNA-Based Assessment of Minimal Residual Disease in Colorectal Cancer: Prognostic and Predictive Implications.
  22. Mutations and selection in normal tissues after cancer treatment.
  23. Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
  24. Beyond the baseline: mapping the context-specific regulatory landscape of disease.
  1. Nat Methods. 2026 Mar;23(3): 542-553
    stVCR: spatiotemporal dynamics of single cells.
    Qiangwei Peng, Peijie Zhou, Tiejun Li.
      Time-series spatial transcriptomics with single-cell resolution provides an opportunity to study cell differentiation, proliferation and migration in physical space over time. However, because sequencing is destructive, reconstructing spatiotemporal dynamics from snapshots remains challenging. In particular, inferring migration is difficult because samples collected at different time points often lie in different coordinate systems across biological replicates. Here we show that spatiotemporal video cassette recorder (stVCR), a generative deep-learning framework, can reconstruct continuous cell differentiation, proliferation, physical-space migration and spatial alignment in an end-to-end manner. The model integrates dynamical optimal transport in an unbalanced setting, density matching that is invariant to rigid transformations, and biologically informed priors to preserve spatial structure. stVCR also enables interpretable analysis of how phenotype transitions interact with spatial migration and proliferation. Using both simulated and real datasets, we demonstrate that stVCR is effective and robust, and we apply it to uncover spatiotemporal dynamics in axolotl brain regeneration and 3D Drosophila embryo development.
    DOI:  https://doi.org/10.1038/s41592-026-03010-3
  2. Nat Rev Genet. 2026 Mar 09.
    Gene regulatory networks: from correlative models to causal explanations.
    Rory J Maizels, James Briscoe.
      Gene regulatory networks (GRNs) explain how the genome controls cellular behaviour and tissue morphogenesis, serving to connect molecular mechanism to functional output. Single-cell technologies now provide descriptions of these networks with unprecedented detail, but this advance has also revealed gene regulatory systems that are too complex for our existing conceptual frameworks. GRNs, which should provide mechanistic explanations, are increasingly reduced to statistical correlations - 'hairballs' that fail to capture molecular causation. Here, we explore why this dilemma exists and propose a path forward. We argue that methods in 'representation learning' can be used to model GRNs, without needing to capture every molecular detail. For this framework, we advocate three linked principles: models must be inherently mechanistic, with structures grounded in cellular and evolutionary biology; molecular principles and constraints must be used to reduce the solution space for learning GRN models; and more sophisticated forms of experimental perturbation and synthetic biological engineering are needed to train models and test predictions. By reimagining GRNs through these principles, we can bridge the gap from data abundance to new conceptual understanding.
    DOI:  https://doi.org/10.1038/s41576-026-00939-1
  3. BMJ Health Care Inform. 2026 Mar 10. pii: e101780. [Epub ahead of print]33(1):
    Comparison of large language models and expert multidisciplinary team decisions in colorectal cancer.
    Boyang Qu, Longhao Cao, Chen Wu, Yongjiu Chen, Tingting Sun, Junpeng Pei, Lei Huang, Xiaotong Hou, Dawei Li, Aiwen Wu.
       OBJECTIVES: To evaluate the ability of large language models (LLMs) to simulate multidisciplinary team (MDT) decision-making in colorectal cancer, a malignancy that often requires complex treatment planning.
    METHODS: We retrospectively analysed 1423 colorectal cancer cases discussed at MDT meetings at Peking University Cancer Hospital between January 2023 and December 2024. Three LLMs-OpenAI o3-mini-2025-01-31, DeepSeek-R1 671b and Qwen qwq-plus-2025-03-05-were tested for their ability to replicate MDT recommendations using a standardised treatment categorisation framework. Each case was processed three times per model; only cases with consistent outputs across all three runs were included. Concordance between AI-generated decisions and expert MDT consensus was assessed using agreement percentages and Cohen's kappa.
    RESULTS: O3 demonstrated the highest intramodel stability, with an agreement rate of 81.0% (Fleiss' kappa=0.794), yielding 1153 cases with consistent outputs. Concordance with MDT consensus was comparable across the three models, ranging from 62.5% to 65.4%. Multivariable analysis of O3 outputs identified treatment-naïve status, non-metastatic disease and colon tumour location as independent predictors of higher concordance with experts.
    DISCUSSION: LLMs showed fair overall agreement with expert MDT decisions, with stronger performance in standardised and less complex clinical scenarios. Areas of higher concordance included treatment-naïve non-metastatic colon cancer, treated non-metastatic rectal cancer and treated non-metastatic colon cancer.
    CONCLUSION: LLMs can partially replicate expert MDT recommendations in colorectal cancer. Their integration into clinical workflows should aim to complement, rather than replace, human expertise.
    Keywords:  Colorectal Tumors
    DOI:  https://doi.org/10.1136/bmjhci-2025-101780
  4. Ann Coloproctol. 2026 Feb;42(1): 72-85
    Gut microbiome in colorectal cancer: recent advances and clinical implications.
    Jun Yong Han, Min Jung Kim, Ji Won Park, Seung-Yong Jeong.
      The gut microbiome is not just a bystander of colorectal carcinogenesis but is an active driver of colorectal cancer (CRC). CRC-associated microbiome contributes in the tumorigenesis through chronic inflammation, formation of toxic metabolite and genotoxins, oncogenic signal activation, immune evasion, and barrier disruption-all reinforcing a tumor microenvironment. In contrast, beneficial microbiome supports the barrier-immune-metabolic axis by maintaining mucosal integrity and balanced immune tone. Despite extensive studies of microbiome-based CRC biomarkers, microbiome-based CRC biomarkers have not been yet ready for routine clinical use due to variation across populations and lack of standardization of key steps such as sampling, analysis, cutoffs, and interpretation. Microbiome-based therapies aim to change the overall intestinal ecosystem rather than simply adding or removing single strains. At present, dietary modulation and prebiotics are considered supportive measures, while probiotics or synbiotics are in preclinical stage. Fecal microbiota transplantation (FMT) still faces important challenges in effectiveness, standardization and safety. By its role in reshaping the tumor-host immune environment, FMT is viewed as a potential option for cancer therapy after further development through well-controlled clinical trials with careful safety monitoring.
    Keywords:  Biomarkers; Carcinogenesis; Colorectal neoplasms; Gastrointestinal microbiome
    DOI:  https://doi.org/10.3393/ac.2026.00010.0001
  5. Mol Clin Oncol. 2026 Apr;24(4): 26
    Research advances in early screening for colorectal cancer (Review).
    Jiaojiao Jiang.
      Early detection and intervention for colorectal cancer (CRC) play crucial roles in reducing the disease burden. However, existing screening methods remain limited in terms of sensitivity, specificity, and compliance. The present review systematically examines and compares cutting-edge research in the field of early screening for CRC performed in recent years, evaluates mainstream screening technologies from multiple dimensions, and provides a theoretical reference basis for the construction of efficient, accurate and sustainable early CRC screening strategies.
    Keywords:  colerectal cancer; screening
    DOI:  https://doi.org/10.3892/mco.2026.2935
  6. Annu Rev Immunol. 2026 Mar 13.
    Immune Niches in Cancer.
    Nadine Slingerland, Eline Runderkamp, Daniela S Thommen.
      Emerging evidence underscores a key role for the tumor microenvironment in supporting or suppressing cancer immunity. Of note, pro- and antitumor immune activity is controlled by not only the types of immune cells present but also their spatial arrangement within a tumor. This evidence is supported by the observation that the organization of immune cells in specialized immune niches is more predictive for clinical outcome and immunotherapy response than is the mere presence of tumor immune infiltrates. In this review, we explore how spatial compartmentalization modulates immune function through concerted cellular interactions, localized signaling cascades, and the generation of protective environments. We integrate current knowledge on both established and emerging immune niches with variable complexity-shaped by cell diversity, cell density, and structural organization-and their functional impact on cancer immunity. Finally, we discuss the compelling therapeutic opportunities offered by the induction or modulation of these niches in tumors.
    DOI:  https://doi.org/10.1146/annurev-immunol-082724-123843
  7. Science. 2026 Mar 12. 391(6790): eadt3439
    Whole-embryo spatial transcriptomics at subcellular resolution from gastrulation to organogenesis.
    Yinan Wan, Jakob El Kholtei, Ignatius Jenie, Mariona Colomer-Rosell, Jialin Liu, Qinghua Zhang, Joaquin Navajas Acedo, Lucia Y Du, Mireia Codina-Tobias, Mengfan Wang, Wei Zheng, Edward Lin, Tzy-Harn Chuang, Oded Mayseless, Ahilya Sawh, Susan E Mango, Guoqiang Yu, Bogdan Bintu, Alexander F Schier.
      Gene expression patterns underlie development, but their systematic detection in whole embryos has remained elusive. We introduce a whole-embryo imaging platform using multiplexed error-robust fluorescent in situ hybridization (weMERFISH). We quantified the expression of 495 genes in zebrafish embryos at subcellular resolution and generated an online atlas detailing the expression of 25,872 genes and accessibility of 294,954 chromatin regions during embryogenesis. Expression patterns often corresponded to composites of tissue-specific accessible elements, and expression changes aligned with cellular maturation and morphogenesis. Integration with live imaging revealed how similar expression patterns can emerge through different dynamics and showed that sharp boundaries develop through changes in gene expression rather than through cell sorting. These results establish multiplexed whole-embryo spatial transcriptomics and reveal the regulation and dynamics of embryonic gene expression patterns.
    DOI:  https://doi.org/10.1126/science.adt3439
  8. Cancer Res. 2026 Mar 12.
    PI3K and MAPK Signaling Nodes Serve as Divergent Drivers of Phenotypic Plasticity in Cancer-Associated Fibroblasts in Colorectal Cancer.
    Zihan Xia, Felix De Vuyst, Sam Ernst, Ujjwal Suwal, Amélie Vander Cruyssen, Pekka Rappu, Jyrki Heino, Sandor Dedeyne, Wim Ceelen, Ligia Craciun, Pieter Demetter, An Hendrix, Olivier De Wever.
      Cancer-associated fibroblasts (CAFs) exhibit phenotypic heterogeneity with each functional state playing critical roles in tumor progression. Notably, subtypes like inflammatory CAFs (iCAFs), characterized by increased chemokine/cytokine secretion, and myofibroblast-like CAFs (myCAFs), characterized by enhanced extracellular matrix (ECM) deposition and increased actomyosin contractility, can undergo phenotypic switching in response to cues from the tumor microenvironment (TME) and therapeutic interventions. Elucidation of the signaling pathways associated with the diverse phenotypes could enable development of strategies to therapeutically reprogram CAFs. Through the analysis of single-cell RNA sequencing data from colorectal cancer (CRC) patients, we identified that the PI3K/mTOR and MAPK/ERK signaling pathways, among other pathways, are linked to the formation of myCAF and iCAF subtypes, respectively. Unbiased pharmacological interference of 12 distinct signaling pathways using three-dimensional (3D) human CRC-derived CAF cultures, ex vivo patient-derived tumor fragments, and mouse models further revealed the significance of PI3K/mTOR and MAPK/ERK signaling in CAF plasticity and functional behavior. PI3K/mTOR inhibition drove iCAF formation through compensatory FGF-2 release and FGFR1-JAK2-STAT3 activation, leading to chemokine/cytokine secretion that promoted tumor spheroid growth and neutrophil infiltration. Conversely, MEK inhibition induced a myCAF phenotype via interferon-dependent ROCK and JAK1 signaling, resulting in ECM production that enhanced tumor colony formation. In summary, these findings reveal a functional significance of PI3K/mTOR and MAPK/ERK signaling pathways in CAF plasticity and underscore how standard-of-care targeted therapies can directly influence CAF phenotypes in CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0766
  9. NPJ Syst Biol Appl. 2026 Mar 11.
    Stochastic modeling of epigenetic memory.
    Simone Bruno, Domitilla Del Vecchio.
      Here, we review mathematical models of epigenetic memory, focusing on chromatin modifications as key mechanisms to achieve long-term maintenance of epigenetic states. After reviewing the main stochastic modeling frameworks, we focus on stochastic models of chromatin modifications to analyze residence time in memory states, which underpins the long-term maintenance of epigenetic information. We review these concepts through increasingly complicated chromatin modification circuits, including histone modifications, DNA methylation, and their combination.
    DOI:  https://doi.org/10.1038/s41540-026-00664-9
  10. J Adv Res. 2026 Mar 06. pii: S2090-1232(26)00190-6. [Epub ahead of print]
    Organoids revolutionizing precancer research.
    Xinyi Han, Lingwei Ma, Jiahui Dai, Dong Gao, Wei Wang.
       BACKGROUND: Precancerous lesions are pivotal intermediates in tumorigenesis, creating critical windows for early detection and intervention. However, research has been hindered by limited clinical samples, pronounced molecular heterogeneity, and the absence of models that faithfully mirror in vivo pathology. Organoids have emerged as a powerful solution, preserving patient-specific genetic, phenotypic, and microenvironmental features while enabling long-term culture and functional interrogation.
    AIM OF REVIEW: This review aims to systematically synthesize recent advances in organoid-based modeling of precancerous lesions. We summarize the latest progress in organoid construction strategies, validation frameworks, and multidimensional applications, including mechanistic dissection of precancerous evolution, biomarker discovery for early detection, and therapeutic screening for precision prevention. Furthermore, we highlight integrative approaches that combine CRISPR-mediated genome editing and single-cell multi-omics to enhance the fidelity, scalability, and clinical relevance of organoid systems in precancer research.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: Organoid technology is reshaping paradigms in precancer research by bridging fundamental biology with clinical translation, providing unprecedented tools for early detection, risk stratification, and personalized cancer prevention.
    Keywords:  Early cancer; Mechanism; Organoids; Precancer; Precision medicine
    DOI:  https://doi.org/10.1016/j.jare.2026.02.055
  11. Nat Methods. 2026 Mar;23(3): 481
    An update on spatial proteomics.
      
    DOI:  https://doi.org/10.1038/s41592-026-03046-5
  12. Discov Oncol. 2026 Mar 11.
    Pericytes and mesenchymal stromal cells converge toward pro-tumor phenotypes in the tumor microenvironment.
    Enrico La Spina, Cesarina Giallongo, Lucia Longhitano, Jessica Ferrigno, Giuseppe Di Rosa, Vittorio Del Fabro, Deborah Calvo, Sebastiano Giallongo, Davide Romano, Andrea Duminuco, Giuseppe A Palumbo, Fabio Galvano, Giovanni Li Volti, Ignazio A Barbagallo, Daniele Tibullo.
      Mesenchymal Stromal Cells (MSCs) and pericytes, although a minor cellular component of the tumor microenvironment (TME), exert outsized control over cancer progression, metastasis, and therapeutic response across both solid and hematologic malignancies. Once separated by functional and anatomical criteria, Single-cell RNA sequencing (scRNA seq) analyses and context-dependent phenotypic transitions - pericyte-to Cancer-Associated Fibroblasts (CAFs) and MSCs-to-CAFs, now blur these classical distinctions, revealing fluid entities and substantial functional convergence. We synthesize current evidence showing that MSCs and pericytes frequently adopt overlapping pro-angiogenic, immunosuppressive, and pro-invasive states driven by PDGF-B/PDGFRβ, TGF-β, CXCL12, and Notch/ROCK signaling. Across cancers, their roles are multifaceted: in Colorectal Cancer (CRC) from neo-vascularization and Drug Resistance (DR) to blood vessel formation, invasion, and metastatic spread. Moreover, MSCs reinforce immunosuppression, whereas pericyte phenotype switching may sensitize tumors to immunotherapy, thus playing a pivotal role in fibrosis-driven cancer progression. In hematologic malignancies, particularly in the Bone Marrow (BM) niche, MSCs sustain leukemic cell survival and DR. Shared markers and transcriptomic signatures, coupled with striking plasticity, underscore their central role in shaping a pro-tumorigenic milieu. This convergence helps to explain the limits of current approaches-such as anti-VEGF monotherapy and supports new strategies. Enhancing pericyte maturity or intercepting transitions toward CAFs are promising avenues to boost treatment efficacy. We propose a practical framework for classifying "MSC-pericyte states" in the TME and emphasize rigorous, multi-marker, spatially resolved analyses to dissect their complex functions, thus opening a new scenario for targeted therapies.
    Keywords:  Mesenchymal stromal cells; Pericytes; TME
    DOI:  https://doi.org/10.1007/s12672-026-04790-y
  13. Science. 2026 Mar 12. 391(6790): 1090-1091
    How will we know if AI is smart enough to do science?
    Celina Zhao.
      New tests gauge whether large language models can use their troves of knowledge to actually make discoveries.
    DOI:  https://doi.org/10.1126/science.aeh1091
  14. Nat Chem Biol. 2026 Mar 11.
    Genetic recording and in situ readout of single-cell signaling memory.
    Kai Hao, Yunzheng Liu, Mykel Barrett, Zainalabedin Samadi, Amirhossein Zarezadeh, Yuka McGrath, Magdalena Zernicka-Goetz, Amjad Askary.
      Intensity and duration of biological signals encode a few pathways to direct diverse cellular behaviors, yet quantifying these features in single cells remains difficult. To address this challenge, we developed INSCRIBE, which uses a CRISPR base editor to mutate genomic targets at rates proportional to signaling activity. Edits are recovered at the endpoint through a new ratiometric readout strategy from images of two fluorescence channels. We engineered human cells to record WNT and BMP activity. Following defined exogenous stimulations, INSCRIBE accurately recovered signal intensity in dose-response experiments and exposure duration in time-course experiments. Applying INSCRIBE revealed a persistent memory in the BMP pathway, where progeny of high-responding cells remained more sensitive to subsequent BMP stimulation for up to 3 weeks. Together, our results establish a scalable platform for genetic recording and in situ readout of signaling activity in single cells, advancing quantitative analysis of cell-cell communication during development and disease.
    DOI:  https://doi.org/10.1038/s41589-026-02168-3
  15. Science. 2026 Mar 12. 391(6790): 1161-1166
    Cancer interception with KRAS inhibitors in preclinical models of pancreatic ductal adenocarcinoma.
    Minh T Than, Lucie Dequiedt, Rina Sor, Shreya Nair, Nune Markosyan, Emma E Furth, Chenghua Yang, Courtney Ray-Fofana, Marie Menard, Elsa Quintana, A Cole Edwards, Connor J Hennessey, Austin L Good, Liz Quinones, Yunseo Hwang, Cynthia Clendenin, Ashley L Kiemen, Robert H Vonderheide, Ben Z Stanger.
      Transformation of pancreatic epithelial cells to malignant pancreatic ductal adenocarcinoma (PDAC) typically involves the progression of precancerous pancreatic intraepithelial neoplasia (PanINs) bearing oncogenic KRAS mutations. Here, we tested the impact of PDAC interception using either RAS(ON) multiselective or RAS(ON) G12D-selective pharmacological inhibitors [RAS(ON) inhibitors] in mouse models of PDAC. Treatment of PanIN-bearing mice with RAS(ON) inhibitors prompted regression of premalignant lesions that translated into a delay in tumor onset and an increase in overall survival (OS). Long-term interception in tumor-prone mice resulted in a median OS of more than 1 year compared with less than 5 months in nonintercepted control mice (P < 0.0001). Comparing the survival benefits of RAS(ON) inhibition for cancer interception versus RAS(ON) inhibition for cancer treatment, we found that interception provided a greater survival benefit to mice. These findings suggest that a pharmacological approach may reduce premalignant burden and increase survival in PDAC.
    DOI:  https://doi.org/10.1126/science.aec7929
  16. Trends Pharmacol Sci. 2026 Mar 11. pii: S0165-6147(26)00017-9. [Epub ahead of print]
    Targeting metabolism to combat anticancer and antibacterial drug resistance.
    Carolina H Chung, Rupa Bhowmick, Annie J Badenoch, Harkirat S Arora, Sriram Chandrasekaran.
      Drug resistance is a major challenge in cancer and infectious diseases, requiring innovative solutions. Recent research suggests that bacteria and cancer cells reprogram their metabolism and manipulate their external metabolic environment to resist a diverse range of therapeutics. Emerging technologies, including single-cell and spatial omics profiling, CRISPR chemogenomics, machine learning, and metabolic network modeling, have revealed the metabolic complexities within bacterial biofilms, tuberculosis granulomas, and the tumor microenvironment. Here, we examine metabolic mechanisms that aid drug resistance across these different disease areas; this includes activation of antioxidant defenses, manipulation of the host immune response, and rewiring of energy metabolism. This analysis of shared metabolic factors across diseases may inspire repurposing of drugs, immunotherapies, and dietary interventions to overcome resistance.
    Keywords:  bacterial infections; cancer; cell metabolism; drug repurposing; drug resistance; systems biology
    DOI:  https://doi.org/10.1016/j.tips.2026.01.013
  17. Trends Cancer. 2026 Mar 10. pii: S2405-8033(26)00036-1. [Epub ahead of print]
    Advancements in organoid models emulating metastatic niches.
    Zora Baumann, Eric Billy, Manuel C Scheidmann.
      Metastases cause most cancer-related deaths, underscoring the need for therapies targeting metastatic stages, including the tumor microenvironment. Yet translating biological insights into treatments remains difficult. Preclinical metastasis research largely relies on rodent models, which have species-specific limitations and are incompatible with large-scale perturbation screens in a human context. Human organoids aim to emulate organ microenvironments in vitro and, when cocultured with cancer cells, can provide complementary models. These 'chimeroids' may enable scalable studies of cancer-microenvironment interactions and support genetic and pharmacological screens to discover new targets, offering insights into the final, often lethal step of metastasis-tissue colonization. This review summarizes advances in stem cell-derived organoid models for organs frequently affected by solid tumor metastases, including the brain, lung, liver, and bone, and evaluates their ability to recreate physiologically relevant niches for studying cancer cell adaptation and colonization.
    Keywords:  chimeroid cocultures; drug development; metastasis; metastatic microenvironment; organoids; target identification
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.005
  18. Nat Rev Genet. 2026 Mar 11.
    Next-generation programmable cell therapies for precision medicine.
    Ana Palma Teixeira, Dominique Aubel, Martin Fussenegger.
      Engineered cell therapies are transforming precision medicine by enabling real-time, context-responsive interventions that act upon disease-specific cues. Inspired by the success of CAR-T cells in oncology, next-generation platforms are being developed using diverse immune cells and stem cells to address a broader spectrum of diseases. These living therapeutics harness synthetic gene circuits to induce targeted cytotoxicity, to modulate the secretion of effector proteins or to coordinate both functions in response to endogenous signals or externally delivered molecular and physical triggers. Ex vivo engineering of autologous cells remains the norm, but challenges in scalability, cost and accessibility are fuelling efforts towards allogeneic products and in vivo reprogramming. Advances in targeted delivery - using viral vectors, mRNA-loaded nanoparticles and virus-like particles - are expanding the toolkit for direct programming of cells within the body. This Review discusses emerging strategies for engineering human cells with therapeutic functions, highlighting modular control systems, delivery innovations and the translational hurdles that lie ahead.
    DOI:  https://doi.org/10.1038/s41576-026-00945-3
  19. Cancer Cell. 2026 Mar 12. pii: S1535-6108(26)00109-1. [Epub ahead of print]
    Toward a consensus on the tumor microbiota: Evidence, standards, and interpretation.
    Tingting Duan, Aviel Rosenbaum, Vidhi Chandra, Luca Tiraboschi, Maria Rescigno, Florencia McAllister, Ravid Straussman, Marlies Meisel.
      Tumors across diverse organs harbor microbial communities that can shape cancer biology and therapeutic responses, yet the field remains polarized by technical and interpretive challenges. In this commentary, we synthesize functional and mechanistic evidence linking intratumoral microbes to cancer hallmarks; critically evaluate current detection approaches; and propose minimal technical and reporting standards to establish microbial presence, viability, and causality. We highlight common pitfalls and outline priorities to move the tumor microbiota field toward robust, clinically actionable insights.
    DOI:  https://doi.org/10.1016/j.ccell.2026.02.011
  20. Nature. 2026 Mar 11.
    Ageing promotes metastasis via activation of the integrated stress response.
    Angana A H Patel, Jozefina J Dzanan, Kevin X Ali, Ella A Eklund, Samantha W Alvarez, Dorota Raj, Martin Dankis, Ilayda Altinönder, Maria Schwarz, Kristell Le Gal, Emre Bedel, Ahmed Ezat El Zowalaty, Emma Jonasson, Heba Albatrok, Nadia Gul, Jozef P Bossowski, Ray Pillai, Patrick Micke, Johan Botling, Levent M Akyürek, Davide Angeletti, Sama I Sayin, Anetta Härtlova, Thales Papagiannakopoulos, Roger Olofsson Bagge, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel, Volkan I Sayin.
      Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-026-10216-0
  21. Cancers (Basel). 2026 Feb 26. pii: 754. [Epub ahead of print]18(5):
    Circulating Tumor DNA-Based Assessment of Minimal Residual Disease in Colorectal Cancer: Prognostic and Predictive Implications.
    Ahmet Anil Ozluk, Will Colley, Zeynep Beyza Arik, Osman Kostek, Aakash Sunkari, Midhun Malla, Mehmet Akce.
      Circulating tumor DNA (ctDNA) has emerged as a promising and versatile biomarker in colorectal cancer (CRC), providing real-time insights into the tumor burden, minimal residual disease (MRD), and treatment response across both early and metastatic stages. In patients with resected stage II-III CRC, post-operative ctDNA positivity is a robust predictor of recurrence and may outperform traditional clinicopathologic risk factors. It can facilitate adjuvant therapy discussions; however, treatment escalation or de-escalation based solely on ctDNA results is not yet supported by available interventional data. In the metastatic setting, ctDNA-based techniques could provide non-invasive molecular profiling and a monitoring response to systemic therapies. Peripheral blood-based techniques could also help detect emerging resistance to systemic therapy. Emerging evidence highlights that quantitative assessment of ctDNA dynamics, including the baseline burden and post-treatment clearance, could further refine risk stratification and inform treatment personalization. Collectively, ctDNA represents a promising and evolving biomarker with well-established prognostic and emerging predictive potential and is poised to support precision oncology across the continuum of CRC.
    Keywords:  circulating tumor DNA; colorectal cancer; minimal residual disease; precision oncology; predictive biomarker; prognostic biomarker
    DOI:  https://doi.org/10.3390/cancers18050754
  22. Nat Genet. 2026 Mar;58(3): 472
    Mutations and selection in normal tissues after cancer treatment.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-026-02557-3
  23. bioRxiv. 2026 Feb 28. pii: 2026.02.26.708335. [Epub ahead of print]
    Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
    Seungmin Yoo, Christopher Young, Liying Li, Lingraj Vannur, Junming Zhuang, Fan Zheng, Meiying Wu, Julie K Andersen, Chuankai Zhou.
      Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.
    DOI:  https://doi.org/10.64898/2026.02.26.708335
  24. Trends Genet. 2026 Mar 12. pii: S0168-9525(26)00010-7. [Epub ahead of print]
    Beyond the baseline: mapping the context-specific regulatory landscape of disease.
    Yoav Gilad, Alexis Battle.
      Genome-wide association studies have identified thousands of intergenic variants associated with disease, most of which are presumed to act by affecting gene regulation. Standard expression quantitative trait locus (eQTL) studies were able to link many disease-associated loci to changes in gene expression. Yet, many disease-associated loci show no detectable regulatory effects in baseline bulk gene expression datasets from adult tissues. Recent work shows that, overall, standard eQTLs differ systematically from disease-associated loci, pointing to regulatory effects not captured under baseline conditions. We review emerging evidence that context-specific eQTLs, revealed under environmental perturbations, stress, or developmental transitions, resemble disease loci more closely. We highlight new in vitro systems and machine learning approaches that promise systematic identification of these context-dependent effects.
    DOI:  https://doi.org/10.1016/j.tig.2026.01.010
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