bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–11–16
sixteen papers selected by
Xiao Qin, University of Oxford
  1. Advancing Cancer Biology: Highlights from the 2025 FASEB SRC on Cellular Plasticity in Cancer.
  2. Modeling cell fates across space and time.
  3. CanSig Benchmarks Methods for Reproducible Cancer Cell State Discovery from Single-Cell Transcriptomic Data.
  4. Signal control during tissue regeneration in adult animals.
  5. Human organoids as 3D in vitro platforms for drug discovery: opportunities and challenges.
  6. Benchmarking of multimodal single-cell omics data integration methods.
  7. Metagenomic editing of commensal bacteria in vivo using CRISPR-associated transposases.
  8. A parts list of promoters and gRNA scaffolds for mammalian genome engineering and molecular recording.
  9. Regulators of androgen receptor activity revealed by CRISPR interference screens.
  10. DNA-programmed cell assembly: from cells, tissues to organoids.
  11. CRISPR-Based Functional Genomics in Pluripotent Stem Cells.
  12. One, two, many: how many cells start a tumour?
  13. Impact of the ECM on the Mechanical Memory of Cancer Cells.
  14. Forward genetic screening in engineered colorectal cancer organoids identifies regulators of metastasis.
  15. Metabolite maps reveal spatial gradients in liver and intestinal tissue.
  16. Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer.
  1. Cancer Heterog Plast. 2025 ;2(4):
    Advancing Cancer Biology: Highlights from the 2025 FASEB SRC on Cellular Plasticity in Cancer.
    Hans Clevers, Ankur Sharma, Sendurai A Mani, Anna Golebiewska, Axel Behrens, Wai Leong Tam, Loic P Deleyrolle, Huiping Liu, Karuna Ganesh, Walid T Khaled, Shaheen Sikandar, Terence K Lee, Tyler E Miller, Dean G Tang, Sheila Singh, Vivian S W Li, Justin D Lathia, Stephanie Ma.
      The inaugural FASEB Science Research Conference (SRC) on Cellular Plasticity in Cancer was held in May 2025 in Hong Kong SAR, China. This event brought together leading experts to discuss cutting-edge research centered on cancer cell plasticity. The conference featured comprehensive presentations covering a broad spectrum of topics, including oncofetal reprogramming in tumor development and progression, mechanisms regulating cancer cell plasticity, metabolic reprogramming and its role in tumor progression, cancer cell plasticity during metastasis, cancer stem cell programs within the tumor microenvironment, tumor plasticity and immune evasion, as well as innovative therapeutic strategies aimed at targeting stem cell-like states, modulating cancer cell states, and effectively controlling disease progression. It is anticipated that the insights gained from this meeting will catalyze further advancements in cancer biology and therapy.
    Keywords:  cancer cell plasticity; cancer stem cells; cellular plasticity; immune evasion; phenotypic switching; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.47248/chp2502040018
  2. Nat Methods. 2025 Nov 10.
    Modeling cell fates across space and time.
      
    DOI:  https://doi.org/10.1038/s41592-025-02884-z
  3. Cancer Res. 2025 Nov 13.
    CanSig Benchmarks Methods for Reproducible Cancer Cell State Discovery from Single-Cell Transcriptomic Data.
    Florian Barkmann, Josephine Yates, Paweł Czyż, Agnieszka Kraft, Marc Glettig, Niko Beerenwinkel, Valentina Boeva.
      Single-cell RNA-sequencing (scRNA-seq) facilitates the discovery of gene expression signatures that define cell states across patients, which could be used in patient stratification and precision oncology. However, the lack of standardization in computational methodologies that are used to analyze these data impedes the reproducibility of signature detection. To address this, we developed CanSig, a comprehensive benchmarking tool that evaluates methods for identifying transcriptional signatures in cancer. CanSig integrates metrics for batch correction and biological signal conservation with a transcriptional signature correlation metric to score methods according to signature rediscovery, cross-dataset reproducibility, and clinical relevance. CanSig was applied to thirteen methods on twelve scRNA-seq datasets from five human cancer types-glioblastoma, breast cancer, lung adenocarcinoma, rhabdomyosarcoma, and cutaneous squamous cell carcinoma-representing 185 patients and 174,000 malignant cells. The signatures identified with these methods correlated with clinically relevant outcomes, including patient survival and lymph node metastasis. These results identified Harmony, BBKNN, and fastMNN as the highest-scoring integration methods for discovering shared transcriptional states in cancer. Overall, CanSig provides a standardized, reproducible framework for uncovering clinically relevant cancer cell states in single-cell transcriptomics.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0940
  4. Nat Rev Mol Cell Biol. 2025 Nov 11.
    Signal control during tissue regeneration in adult animals.
    Sushant Bangru, Rocky Diegmiller, Stefano Di Talia, Kenneth D Poss.
      Tissue regeneration has historically been the subject of intense scientific scrutiny, from basic biology to applications in regenerative medicine. Use of model organisms and cutting-edge technologies have uncovered various mechanisms of regeneration, but understanding how signals are regulated spatiotemporally to renew lost structures at scale remains a challenge. Recent insights into chromatin structure and enhancer regulation, immune-tissue crosstalk, bioelectric and metabolic cues and quantitative modelling are broadening and reshaping our understanding of how tissues repair and renew. The evolution of cutting-edge tools for in vivo profiling and tracking of single cells is providing unprecedented dynamic views of regeneration across scales. Here, we synthesize the current knowledge of signal control in regeneration, with emphasis on conceptual advances, technical innovations and future directions for a more quantitative understanding of regenerative biology.
    DOI:  https://doi.org/10.1038/s41580-025-00917-1
  5. Nat Rev Drug Discov. 2025 Nov 12.
    Human organoids as 3D in vitro platforms for drug discovery: opportunities and challenges.
    Daisong Wang, Remi Villenave, Nadine Stokar-Regenscheit, Hans Clevers.
      Organoids are 3D structures derived from stem cells that recapitulate key architectural and functional aspects of the corresponding tissue. Compared with conventional 2D cell lines, human organoids provide experimental models that more closely reflect human physiology. Their ability to capture the complexity and heterogeneity of human tissues enables the study of disease mechanisms, drug efficacy and toxicity. When generated from patient material, organoids also allow the assessment of individual drug responses. In this Review, we explore the utility of organoids in drug discovery. We outline current methodologies for generating and maintaining organoids, examine their applications in disease modelling, drug screening and safety evaluation, and consider regulatory aspects and the challenges for their broader adoption in drug discovery.
    DOI:  https://doi.org/10.1038/s41573-025-01317-y
  6. Nat Genet. 2025 Nov;57(11): 2620
    Benchmarking of multimodal single-cell omics data integration methods.
    Margot Brandt.
      
    DOI:  https://doi.org/10.1038/s41588-025-02437-2
  7. Science. 2025 Nov 13. 390(6774): eadx7604
    Metagenomic editing of commensal bacteria in vivo using CRISPR-associated transposases.
    Diego Rivera Gelsinger, Carlotta Ronda, Junjie Ma, Om B Kar, Madeline Edwards, Yiming Huang, Chrystal F Mavros, Yiwei Sun, Tyler Perdue, Phuc Leo Vo, Ivaylo I Ivanov, Samuel H Sternberg, Harris H Wang.
      Although metagenomic sequencing has revealed a rich microbial biodiversity in the mammalian gut, methods to genetically alter specific species in the microbiome are highly limited. Here, we introduce Metagenomic Editing (MetaEdit) as a platform technology for microbiome engineering that uses optimized CRISPR-associated transposases delivered by a broadly conjugative vector to directly modify diverse native commensal bacteria from mice and humans with new pathways at single-nucleotide genomic resolution. Using MetaEdit, we achieved in vivo genetic capture of native murine Bacteroides by integrating a metabolic payload that enables tunable growth control in the mammalian gut with dietary inulin. We further show in vivo editing of segmented filamentous bacteria, an immunomodulatory small-intestinal microbial species recalcitrant to cultivation. Collectively, this work provides a paradigm to precisely manipulate individual bacteria in native communities across gigabases of their metagenomic repertoire.
    DOI:  https://doi.org/10.1126/science.adx7604
  8. Nat Biotechnol. 2025 Nov 11.
    A parts list of promoters and gRNA scaffolds for mammalian genome engineering and molecular recording.
    Troy A McDiarmid, Megan L Taylor, Wei Chen, Florence M Chardon, Junhong Choi, Hanna Liao, Xiaoyi Li, Haedong Kim, Jean-Benoît Lalanne, Tony Li, Jenny F Nathans, Beth K Martin, Jordan Knuth, Alessandro L V Coradini, Jesse M Gray, Sudarshan Pinglay, Jay Shendure.
      A standardized 'parts list' of sequences for genetic engineering of microbes has been indispensable to progress in synthetic biology, but few analogous parts exist for mammalian systems. Here we design libraries of extant, ancestral, mutagenized or miniaturized variants of polymerase III promoters and guide RNA (gRNA) scaffolds and quantify their abilities to mediate precise edits to the mammalian genome through multiplex prime editing. We identify thousands of parts for reproducible editing in human and mouse cell lines, including hundreds with greater activity than commonly used sequences. Saturation mutagenesis screens identify tolerated sequence variants that further enhance sequence diversity. In an application to molecular recording, we design a 'ten key' array that, in mammalian cells, achieves balanced activity of pegRNAs as predicted by the activity of the component parts. The data reported here will aid the design of synthetic loci encoding arrays of gRNAs exhibiting predictable, differentiated levels of activity for applications in multiplexed perturbation, biological recorders and complex genetic circuits.
    DOI:  https://doi.org/10.1038/s41587-025-02896-2
  9. Nat Genet. 2025 Nov 12.
    Regulators of androgen receptor activity revealed by CRISPR interference screens.
      
    DOI:  https://doi.org/10.1038/s41588-025-02432-7
  10. Front Bioeng Biotechnol. 2025 ;13 1716071
    DNA-programmed cell assembly: from cells, tissues to organoids.
    Zhenyi Chen, Pan Fu, Kaizhe Wang.
      The precise spatial organization of cells into functional tissues represents a fundamental challenge in biology and regenerative medicine. Conventional methods for directing cell assembly often lack the specificity, reproducibility, and dynamic control necessary to mimic native tissue architectures. This review explores the emerging use of DNA as a programmable and biocompatible strategy to engineer cell-cell interactions and construct hierarchically ordered tissue models. We first introduce the properties of various DNA toolbox and their strategies for cell modification and assembly. Importantly, we highlight the latest research advances in DNA-encoded cell spheroids, layered tissues, and organoids. Finally, we summarize current challenges and future directions in DNA-programmed assembly.
    Keywords:  DNA nanomaterials; cell assembly; cell engineering; cell-cell interactions; organoids; tissue models
    DOI:  https://doi.org/10.3389/fbioe.2025.1716071
  11. Stem Cell Rev Rep. 2025 Nov 14.
    CRISPR-Based Functional Genomics in Pluripotent Stem Cells.
    Setareh Zahedi.
      The integration of CRISPR-based functional genomics with pluripotent stem cell (PSC) technologies has been recognized as a transformative approach for investigating gene function, modeling human disease, and advancing regenerative medicine. The aim of this review is to provide a comprehensive evaluation of recent developments in CRISPR-Cas platforms, including gene knockouts, base and prime editing, and CRISPR activation or interference (CRISPRa/i), as applied to PSC systems. Studies employing human PSCs, including embryonic stem cells and induced pluripotent stem cells, have been examined to summarize methodologies for genome-wide screening, lineage tracing, and therapeutic engineering. Advances in editing efficiency, delivery strategies, and genomic safety have been reported, while limitations persist in the form of off-target modifications, epigenetic variability, and cell-type-specific responses. Notable applications include the generation of immune-evasive PSC lines, the development of organoid models for physiological and pathological studies, and the implementation of phenotypic screening for disease-relevant traits. Collectively, these technological and methodological advancements have established functional genomics of PSC-CRISPRSPR as a versatile and powerful framework for elucidating fundamental aspects of human biology, dissecting complex traits, and accelerating the translation of discoveries from experimental research to clinical implementation.
    Keywords:  CRISPR; CRISPR-Cas systems; Embryonic stem cells; Functional genomics; Genome editing; Induced pluripotent stem cells; Pluripotent stem cells; Regenerative medicine; organoids
    DOI:  https://doi.org/10.1007/s12015-025-11019-y
  12. Nat Rev Cancer. 2025 Nov 14.
    One, two, many: how many cells start a tumour?
    Patricia Basurto-Lozada, Carla Daniela Robles-Espinoza.
      
    DOI:  https://doi.org/10.1038/s41568-025-00895-8
  13. Cells. 2025 Oct 30. pii: 1707. [Epub ahead of print]14(21):
    Impact of the ECM on the Mechanical Memory of Cancer Cells.
    Claudia Tanja Mierke.
      Besides genomic and proteomic analyses of bulk and individual cancer cells, cancer research focuses on the mechanical analysis of cancers, such as cancer cells. Throughout the oncogenic evolution of cancer, mechanical inputs are stored as epigenetic memory, which ensures versatile coding of malignant characteristics and a quicker response to external environmental influences in comparison to solely mutation-based clonal evolutionary mechanisms. Cancer's mechanical memory is a proposed mechanism for how complex details such as metastatic phenotypes, treatment resistance, and the interaction of cancers with their environment could be stored at multiple levels. The mechanism appears to be similar to the formation of memories in the brain and immune system like epigenetic alterations in individual cells and scattered state changes in groups of cells. Carcinogenesis could therefore be the outcome of physiological multistage feedback mechanisms triggered by specific heritable oncogenic alterations, resulting in a tumor-specific disruption of the integration of the target site/tissue into the overall organism. This review highlights and discusses the impact of the ECM on cancer cells' mechanical memory during their metastatic spread. Additionally, it demonstrates how the emergence of a mechanical memory of cancer can give rise to new degrees of individuality within the host organism, and a connection to the cancer entity is established by discussing a connection to the metastasis cascade. The aim is to identify common mechanical memory mechanisms of different types of cancer. Finally, it is emphasized that efforts to identify the malignant potency of tumors should go way beyond sequencing approaches and include a functional diagnosis of cancer physiology and a dynamic mechanical assessment of cancer cells.
    Keywords:  deformability; environmental mechanical cues; epigenetics; mechanical memory; mechanobiology; stiffness; traction forces; viscoelasticity
    DOI:  https://doi.org/10.3390/cells14211707
  14. Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2510910122
    Forward genetic screening in engineered colorectal cancer organoids identifies regulators of metastasis.
    Xin Wang, Zvi Cramer, Nicolae Adrian Leu, Keara Monaghan, Kayla Durning, Stephanie Adams-Tzivelekidis, Joshua H Rhoades, Jonathan Heintz, Yuhua Tian, Joshua Rico, Diego Mendez, Ricardo Petroni, Austin C King, Melissa S Kim, Rina Matsuda, Olivia Hanselman, Alice E Shin, María F Carrera Rodríguez, Igor E Brodsky, Anil Rustgi, Ning Li, Christopher J Lengner, M Andrés Blanco.
      Metastatic outgrowth requires that cancer cells delaminate from the primary tumor, intravasate, survive in circulation, extravasate, migrate to, and proliferate at a distal site. Recurrent genetic drivers of metastasis remain elusive, suggesting that unlike the early steps of oncogenesis, metastasis drivers may be variable. We develop a framework for identifying metastasis regulators using CRISPR/Cas9-based screening in a genetically defined organoid model of colorectal adenocarcinoma. We conduct in vitro screens for invasion and migration alongside orthotopic, in vivo screens for gain of metastasis in a syngeneic mouse model. We identify CTNNA1 and BCL2L13 as bona fide metastasis-specific suppressors which do not confer any selective advantage in primary tumors. CTNNA1 loss promotes cell invasion and migration, and BCL2L13 loss promotes anchorage-independent survival and non-cell-autonomous changes to macrophage polarization. This study demonstrates proof of principle that large-scale genetic screening can be performed in tumor-organoid models in vivo and identifies novel regulators of metastasis.
    Keywords:  CRISPR screen; colorectal cancer; metastasis; organoid
    DOI:  https://doi.org/10.1073/pnas.2510910122
  15. Nature. 2025 Nov 12.
    Metabolite maps reveal spatial gradients in liver and intestinal tissue.
      
    Keywords:  Imaging; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-03457-y
  16. Cancer Cell. 2025 Nov 13. pii: S1535-6108(25)00451-9. [Epub ahead of print]
    Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer.
    Yuetong Zhang, Jiaying Chen, Yong She, Zhaoyuan Fang, Yaxin Zhang, Danyun Ruan, Wenjun Guo, Jianping Liao, Weiping Zhou, Jianpei Lao, Weicheng Fang, Xingyan Pan, Wenfei Kang, Zifeng Wang, Yuanzhong Wu, Rong Deng, Lin Tian, Liqin Wang, Huilin Huang, Jian Zheng, Yan Yan, Hezhe Lu, Ruiping Wang, Rona Yaeger, Qi Zhao, Wenting Liao, Feng Wang, Yijun Gao.
      While dual KRAS and epidermal growth factor receptor (EGFR) inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient-derived organoids and xenografts, as well as clinical specimens, we discover that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state-a secretory lineage typically confined to the intestinal crypt. Lineage tracing reveals that CRC cells evade dual therapy by transitioning into a Paneth-like state. Through integrated transcriptomic analysis and CRISPR genetic screening, we identify SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevents the Paneth-like transition, restores drug sensitivity, and synergizes with KRAS-EGFR inhibition across multiple preclinical models. These findings reveal that the SMAD1-FGFR3 axis triggers Paneth-like plasticity to drive KRAS-EGFR dual therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance.
    Keywords:  KRAS mutant colorectal cancer; Paneth-like cell state; drug resistance; dual KRAS and EGFR-targeted therapy; lineage plasticity; trans-differentiation
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.010
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒24 at 19:56.