bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–06–01
ten papers selected by
Xiao Qin, University of Oxford
  1. Single-cell ultra-high-throughput multiplexed chromatin and RNA profiling reveals gene regulatory dynamics.
  2. Cross-tissue multicellular coordination and its rewiring in cancer.
  3. Methods for multiplexing single-cell multi-omics.
  4. Experimental toolkit to study the oncogenic role of WNT signaling in colorectal cancer.
  5. Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation.
  6. Cancer microbiota: a focus on tumor-resident bacteria.
  7. The diverse roles of the circadian clock in cancer.
  8. The pan-cancer proteome atlas, a mass spectrometry-based landscape for discovering tumor biology, biomarkers, and therapeutic targets.
  9. Immune Evasion in Cancer Metastasis: An Unappreciated Role of Monocytes.
  10. Precise measurement of molecular phenotypes with barcode-based CRISPRi systems.
  1. Nat Methods. 2025 May 26.
    Single-cell ultra-high-throughput multiplexed chromatin and RNA profiling reveals gene regulatory dynamics.
    Sara Lobato-Moreno, Umut Yildiz, Annique Claringbould, Nila H Servaas, Evi P Vlachou, Christian Arnold, Hanke Gwendolyn Bauersachs, Víctor Campos-Fornés, Minyoung Kim, Ivan Berest, Karin D Prummel, Kyung-Min Noh, Mikael Marttinen, Judith B Zaugg.
      Enhancers and transcription factors (TFs) are crucial in regulating cellular processes. Current multiomic technologies to study these elements in gene regulatory mechanisms lack multiplexing capability and scalability. Here we present single-cell ultra-high-throughput multiplexed sequencing (SUM-seq) for co-assaying chromatin accessibility and gene expression in single nuclei. SUM-seq enables profiling hundreds of samples at the million cell scale and outperforms current high-throughput single-cell methods. We demonstrate the capability of SUM-seq to (1) resolve temporal gene regulation of macrophage M1 and M2 polarization to bridge TF regulatory networks and immune disease genetic variants, (2) define the regulatory landscape of primary T helper cell subsets and (3) dissect the effect of perturbing lineage TFs via arrayed CRISPR screens in spontaneously differentiating human induced pluripotent stem cells. SUM-seq offers a cost-effective, scalable solution for ultra-high-throughput single-cell multiomic sequencing, accelerating the unraveling of complex gene regulatory networks in cell differentiation, responses to perturbations and disease studies.
    DOI:  https://doi.org/10.1038/s41592-025-02700-8
  2. Nature. 2025 May 28.
    Cross-tissue multicellular coordination and its rewiring in cancer.
    Qiang Shi, Yihan Chen, Yang Li, Shishang Qin, Yu Yang, Yang Gao, Linnan Zhu, Dongfang Wang, Zemin Zhang.
      The multicellular coordination that underlies tissue homeostasis and disease progression is of fundamental interest1-5. However, how diverse cell types are organized within tissue niches for cohesive functioning remains largely unknown. Here we systematically characterized cross-tissue coordinated cellular modules in healthy tissues, uncovering their spatiotemporal dynamics and phenotypic associations, and examined their rewiring in cancer. We first compiled a comprehensive single-cell transcriptomic atlas from 35 human tissues, revealing substantial inter-tissue variability in cellular composition. By leveraging covariance in cellular abundance, we identified 12 cellular modules with distinct cellular compositions, tissue prevalences and spatial organizations, and demonstrated coordinated intercellular communication within cellular modules using in situ spatial and in vivo perturbation data. Among them, two immune cellular modules in the spleen showed contrasting chronological dynamics with ageing. Analysis of multicellular changes in the breast revealed a menopausal trajectory associated with fibroblast dynamics. Furthermore, interrogation across cancer types uncovered simultaneous rewiring of two types of multicellular ecosystem during tumour progression, including the loss of tissue-specific healthy organization and the emergence of a convergent cancerous ecosystem. These findings reveal fundamental organizing principles of multicellular ecosystems in health and cancer, laying a foundation for further investigations into tissue-level functional coordination across diverse contexts.
    DOI:  https://doi.org/10.1038/s41586-025-09053-4
  3. Nat Methods. 2025 May 26.
    Methods for multiplexing single-cell multi-omics.
    Laura C Kida, Caleb A Lareau.
      
    DOI:  https://doi.org/10.1038/s41592-025-02657-8
  4. Biochim Biophys Acta Rev Cancer. 2025 May 23. pii: S0304-419X(25)00096-4. [Epub ahead of print]1880(4): 189354
    Experimental toolkit to study the oncogenic role of WNT signaling in colorectal cancer.
    Pujarini Dash, Vikas Yadav, Biswajit Das, Shakti Ranjan Satapathy.
      Colorectal cancer (CRC) is linked to the WNT/β-catenin signaling as its primary driver. Aberrant activation of WNT/β-catenin signaling is closely correlated with increased incidence, malignancy, poorer prognosis, and even higher cancer-related death. Research over the years has postulated various experimental models that have facilitated an understanding of the complex mechanisms underlying WNT signaling in CRC. In the present review, we have comprehensively summarized the in vitro, in vivo, patient-derived, and computational models used to study the role of WNT signaling in CRC. We discuss the use of CRC cell lines and organoids in capturing the molecular intricacies of WNT signaling and implementing xenograft and genetically engineered mouse models to mimic the tumor microenvironment. Patient-derived models, including xenografts and organoids, provide valuable insights into personalized medicine approaches. Additionally, we elaborated on the role of computational models in simulating WNT signaling dynamics and predicting therapeutic outcomes. By evaluating the advantages and limitations of each model, this review highlights the critical contributions of these systems to our understanding of WNT signaling in CRC. We emphasize the need to integrate diverse model systems to enhance translational research and clinical applications, which is the primary goal of this review.
    Keywords:  Colorectal cancer; Computational models; Mouse models; Organoid models; WNT signaling
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189354
  5. Science. 2025 May 29.
    Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation.
    Ajay S Labade, Zachary D Chiang, Caroline Comenho, Paul L Reginato, Andrew C Payne, Andrew S Earl, Rojesh Shrestha, Fabiana M Duarte, Ehsan Habibi, Ruochi Zhang, George M Church, Edward S Boyden, Fei Chen, Jason D Buenrostro.
      Microscopy and genomics are used to characterize cell function, but approaches to connect the two types of information are lacking, particularly at subnuclear resolution. Here, we describe expansion in situ genome sequencing (ExIGS), a technology that enables sequencing of genomic DNA and superresolution localization of nuclear proteins in single cells. Applying ExIGS to progeria-derived fibroblasts revealed that lamin abnormalities are linked to hotspots of aberrant chromatin regulation that may erode cell identity. Lamin was found to generally repress transcription, suggesting variation in nuclear morphology may affect gene regulation across tissues and aged cells. These results demonstrate that ExIGS may serve as a generalizable platform to link nuclear abnormalities to gene regulation, offering insights into disease mechanisms.
    DOI:  https://doi.org/10.1126/science.adt2781
  6. EMBO Rep. 2025 May 28.
    Cancer microbiota: a focus on tumor-resident bacteria.
    Gerlanda Vella, Maria Rescigno.
      Accumulating evidence highlights the presence of an intratumoral microbiota across various cancer types. Among all the microorganisms comprising the tumor-associated microbiota, tumor-resident bacteria (TRB) are increasingly recognized as critical regulators of cancer biology. Within tumor tissues, these microorganisms interact with various components of the tumor microenvironment (TME) and influence both tumor-promoting and tumor-suppressing pathways, underlying their dual role in cancer. Fully understanding the functional roles of TRB and their complex interactions with components of the TME requires the application of multimodal technologies. Developing strategies to modulate TRB-either by eradicating pathogenic populations or harnessing beneficial ones-holds great promise for advancing cancer treatment. In this review, we summarize the most recent insights into TRB. We discuss their possible origins and their implications on cancer biology, focusing on their roles in cancer development, metastasis establishment, immune modulation, and therapy response. Finally, we describe bacteria-based strategies and address the major challenges in detecting and analyzing these microbial communities in tumors.
    Keywords:  Intratumoral Microbiota; Metastasis; Microbiota; Therapy Efficacy; Tumor Microenvironment
    DOI:  https://doi.org/10.1038/s44319-025-00482-w
  7. Nat Cancer. 2025 May;6(5): 753-767
    The diverse roles of the circadian clock in cancer.
    Bridget M Fortin, Alisa L Mahieu, Rachel C Fellows, Yi Kang, Amber N Lewis, Aya S Ead, Katja A Lamia, Yin Cao, Nicholas R Pannunzio, Selma Masri.
      A growing part of the human population is affected by circadian misalignment caused by deregulated sleep, increased nighttime light exposure and erratic eating patterns. Thus, circadian rhythms are a key research area, with compelling links to cancer. Here, we review the circadian regulation of critical cellular processes, including immunity, metabolism, cell cycle control and DNA repair, under physiological homeostasis and in cancer. We discuss the divergent evidence indicating tissue-specific roles of the circadian clock in different cancer types and the potential link between circadian misalignment and early-onset cancers. Finally, we outline how understanding the circadian clock can improve cancer prevention and chronomedicine-based therapies.
    DOI:  https://doi.org/10.1038/s43018-025-00981-8
  8. Cancer Cell. 2025 May 27. pii: S1535-6108(25)00212-0. [Epub ahead of print]
    The pan-cancer proteome atlas, a mass spectrometry-based landscape for discovering tumor biology, biomarkers, and therapeutic targets.
    Jaco C Knol, Mengge Lyu, Franziska Böttger, Madalena Nunes Monteiro, Thang V Pham, Frank Rolfs, Andrea Vallés-Martí, Tim Schelfhorst, Richard R de Goeij-de Haas, Irene V Bijnsdorp, Shuaiyao Wang, Fangfei Zhang, Jun A, Bart A Westerman, Barbara Sitek, Janne Lehtiö, Jan Koster, Jan N M IJzermans, Hanneke W M van Laarhoven, Maarten F Bijlsma, Jan Paul Medema, Alex A Henneman, Sander R Piersma, Ruud H Brakenhoff, Jacqueline Cloos, Valentina Cordo', Daphne de Jong, Geert Kazemier, Danijela Koppers-Lalic, Mariette Labots, Tessa Y S Le Large, John W M Martens, Jules P P Meijerink, Madiha Mumtaz, Chantal Scheepbouwer, Robby E Kibbelaar, David P Noske, Renske D M Steenbergen, Nicole C T van Grieken, Winan van Houdt, Elisa Giovannetti, Geert J L H van Leenders, Jos Jonkers, Tong Liu, Meisi Yan, Xiaolu Zhan, Tiannan Guo, Connie R Jimenez.
      Most cancer proteomics studies to date have focused on a single cancer type. We report The Pan-Cancer Proteome Atlas (TPCPA) based on data-independent acquisition mass spectrometry, to better understand cancer biology and identify therapeutic targets and biomarkers. TPCPA includes 9,670 proteins derived from 999 primary tumors representing 22 cancer types. We describe pan-cancer and cancer type-enriched proteins with extensive external annotation, prioritizing candidate drug targets and biomarkers. Relevant for proteolysis-targeting chimeras, we identify E3-ubiquitin ligases highly expressed in specific tumor types, including HERC5 (esophageal cancer) and RNF5 (liver cancer). Co-expression analysis reveals 13 modules, including unexpected hub proteins as potential drug targets (e.g., GFPT1, LRPPRC, PINK1, DOCK2, and PTPN6). Analysis of 195 colorectal cancers identifies protein markers for RNA-based consensus molecular subtypes (CMSs) and two immune subtypes with prognostic value. We report a cancer type classifier for identification of cancers of unknown primary origin. All TPCPA data can be queried in a dedicated web resource.
    Keywords:  bioinformatics; biomarker/ target; colorectal cancer subtypes; mass spectrometry; multi-cancer (sub)type classification; pan-cancer; proteome
    DOI:  https://doi.org/10.1016/j.ccell.2025.05.003
  9. Cancers (Basel). 2025 May 12. pii: 1638. [Epub ahead of print]17(10):
    Immune Evasion in Cancer Metastasis: An Unappreciated Role of Monocytes.
    Marina R Patysheva, Anastasya A Fedorenko, Anna A Khozyainova, Evgeny V Denisov, Tatiana S Gerashchenko.
      Metastasis is the leading cause of cancer-related deaths. During the metastatic cascade, cancer cells tightly interact with immune cells influencing each other in the tumor microenvironment and systemically. Monocytes are important components of immune evasion and critical regulators of cancer progression. They circulate through the bloodstream and contribute to the formation of a pro-tumor microenvironment both in the tumor and pre-metastatic niche. Whereas monocyte participation in cancer development and response to therapy has been described extensively, its impact on metastasis remains a completely uncovered area. This review first summarizes data concerning the influence of monocytes on metastasis formation during their presence in the circulation, primary tumor, and pre-metastatic niche. We also highlight the latest examinations into the clinical relevance of targeting monocytes to prevent metastasis.
    Keywords:  epithelial-mesenchymal plasticity; immune evasion; immunotherapy; metastasis; monocyte; monocytic myeloid-derived suppressor cell; pre-metastatic niche; progression; tumor hybrid cell
    DOI:  https://doi.org/10.3390/cancers17101638
  10. Genome Biol. 2025 May 25. 26(1): 142
    Precise measurement of molecular phenotypes with barcode-based CRISPRi systems.
    Joseph H Lobel, Nicholas T Ingolia.
      Genome-wide CRISPR-Cas9 screens have untangled regulatory networks driving diverse biological processes. Their success relies on interrogating specific molecular phenotypes and distinguishing key regulators from background effects. Here, we realize these goals by optimizing CRISPR interference with barcoded expression reporter sequencing (CiBER-seq) to dramatically improve the sensitivity and scope of genome-wide screens. We systematically address technical factors that distort phenotypic measurements by normalizing expression reporters against closely matched promoters. We use our improved CiBER-seq to accurately capture known components of well-studied RNA and protein quality control systems. These results demonstrate the precision and versatility of CiBER-seq for dissecting cellular pathways.
    Keywords:  CIBER-seq; CRISPR/Cas9; Massively parallel reporter assay; Nonsense-mediated decay; Protein quality control
    DOI:  https://doi.org/10.1186/s13059-025-03610-w
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