bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–01–26
eightteen papers selected by
Xiao Qin, University of Oxford
  1. Plasticity in metastatic colorectal cancer.
  2. Mapping cells through time and space with moscot.
  3. Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord.
  4. Multimodal cell mapping with optimal transport.
  5. Mechanisms and technologies in cancer epigenetics.
  6. Cancer vaccines.
  7. Multiscale footprints reveal the organization of cis-regulatory elements.
  8. Refining biomarker design in light of cancer evolution.
  9. Precision control of cellular functions with a temperature-sensitive protein.
  10. SMAD4 and KRAS Status Shape Cancer Cell-Stromal Crosstalk and Therapeutic Response in Pancreatic Cancer.
  11. Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted.
  12. Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer.
  13. Spatiotemporal and genetic cell lineage tracing of endodermal organogenesis at single-cell resolution.
  14. Consensus representation of multiple cell-cell graphs from gene signaling pathways for cell type annotation.
  15. Sequencing technologies to measure translation in single cells.
  16. Single-cell DNA sequencing reveals pervasive positive selection throughout preleukemic evolution.
  17. How to trick the immune system into attacking tumours.
  18. A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer.
  1. Dev Cell. 2025 Jan 20. pii: S1534-5807(24)00757-3. [Epub ahead of print]60(2): 171-173
    Plasticity in metastatic colorectal cancer.
    Frederick J H Whiting, Trevor A Graham.
      Genetic mutations cause colorectal cancer (CRC) initiation, but their contribution to metastasis and therapy resistance is less clear. In a recent issue of Nature, Moorman et al.1 use single-cell transcriptome sequencing to map the changes in cancer cell state (cell phenotypes) that occur through CRC progression.
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.018
  2. Nature. 2025 Jan 22.
    Mapping cells through time and space with moscot.
    Dominik Klein, Giovanni Palla, Marius Lange, Michal Klein, Zoe Piran, Manuel Gander, Laetitia Meng-Papaxanthos, Michael Sterr, Lama Saber, Changying Jing, Aimée Bastidas-Ponce, Perla Cota, Marta Tarquis-Medina, Shrey Parikh, Ilan Gold, Heiko Lickert, Mostafa Bakhti, Mor Nitzan, Marco Cuturi, Fabian J Theis.
      Single-cell genomic technologies enable the multimodal profiling of millions of cells across temporal and spatial dimensions. However, experimental limitations hinder the comprehensive measurement of cells under native temporal dynamics and in their native spatial tissue niche. Optimal transport has emerged as a powerful tool to address these constraints and has facilitated the recovery of the original cellular context1-4. Yet, most optimal transport applications are unable to incorporate multimodal information or scale to single-cell atlases. Here we introduce multi-omics single-cell optimal transport (moscot), a scalable framework for optimal transport in single-cell genomics that supports multimodality across all applications. We demonstrate the capability of moscot to efficiently reconstruct developmental trajectories of 1.7 million cells from mouse embryos across 20 time points. To illustrate the capability of moscot in space, we enrich spatial transcriptomic datasets by mapping multimodal information from single-cell profiles in a mouse liver sample and align multiple coronal sections of the mouse brain. We present moscot.spatiotemporal, an approach that leverages gene-expression data across both spatial and temporal dimensions to uncover the spatiotemporal dynamics of mouse embryogenesis. We also resolve endocrine-lineage relationships of delta and epsilon cells in a previously unpublished mouse, time-resolved pancreas development dataset using paired measurements of gene expression and chromatin accessibility. Our findings are confirmed through experimental validation of NEUROD2 as a regulator of epsilon progenitor cells in a model of human induced pluripotent stem cell islet cell differentiation. Moscot is available as open-source software, accompanied by extensive documentation.
    DOI:  https://doi.org/10.1038/s41586-024-08453-2
  3. bioRxiv. 2025 Jan 11. pii: 2025.01.10.632483. [Epub ahead of print]
    Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord.
    Elena K Kandror, Anqi Wang, Mathieu Carriere, Alexis Peterson, Will Liao, Andreas Tjärnberg, Jun Hou Fung, Krishnaa T Mahbubani, Jackson Loper, William Pangburn, Yuchen Xu, Kourosh Saeb-Parsy, Raul Rabadan, Tom Maniatis, Abbas H Rizvi.
      Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in the human spinal cord at single-cell and single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised and bivalent active transcriptional enhancer states that define cell type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type specific cryptic enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility. Such cryptic enhancers define both stable cell type identity and transitions between cells undergoing differentiation. We also define glial cell gene regulatory networks that reorganize along the rostrocaudal axis, revealing anatomical differences in gene regulation. Finally, we identify the spatial organization of cells into distinct cellular organizations and address the functional significance of this observation in the context of paracrine signaling. We conclude that cellular diversity is best captured through the lens of enhancer state and intercellular interactions that drive transitions in cellular state. This study provides fundamental insights into the cellular organization of the healthy human spinal cord.
    DOI:  https://doi.org/10.1101/2025.01.10.632483
  4. Nature. 2025 Jan 22.
    Multimodal cell mapping with optimal transport.
      
    Keywords:  Cell biology; Computational biology and bioinformatics; Machine learning
    DOI:  https://doi.org/10.1038/d41586-025-00107-1
  5. Front Oncol. 2024 ;14 1513654
    Mechanisms and technologies in cancer epigenetics.
    Zaki A Sherif, Olorunseun O Ogunwobi, Habtom W Ressom.
      Cancer's epigenetic landscape, a labyrinthine tapestry of molecular modifications, has long captivated researchers with its profound influence on gene expression and cellular fate. This review discusses the intricate mechanisms underlying cancer epigenetics, unraveling the complex interplay between DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. We navigate through the tumultuous seas of epigenetic dysregulation, exploring how these processes conspire to silence tumor suppressors and unleash oncogenic potential. The narrative pivots to cutting-edge technologies, revolutionizing our ability to decode the epigenome. From the granular insights of single-cell epigenomics to the holistic view offered by multi-omics approaches, we examine how these tools are reshaping our understanding of tumor heterogeneity and evolution. The review also highlights emerging techniques, such as spatial epigenomics and long-read sequencing, which promise to unveil the hidden dimensions of epigenetic regulation. Finally, we probed the transformative potential of CRISPR-based epigenome editing and computational analysis to transmute raw data into biological insights. This study seeks to synthesize a comprehensive yet nuanced understanding of the contemporary landscape and future directions of cancer epigenetic research.
    Keywords:  DNA methylation; cancer; chromatin; epigenetic therapy; epigenetics; histone modifications; non-coding RNAs; tumorigenesis
    DOI:  https://doi.org/10.3389/fonc.2024.1513654
  6. Nat Biotechnol. 2025 Jan;43(1): 29
    Cancer vaccines.
      
    DOI:  https://doi.org/10.1038/s41587-024-02521-8
  7. Nature. 2025 Jan 22.
    Multiscale footprints reveal the organization of cis-regulatory elements.
    Yan Hu, Max A Horlbeck, Ruochi Zhang, Sai Ma, Rojesh Shrestha, Vinay K Kartha, Fabiana M Duarte, Conrad Hock, Rachel E Savage, Ajay Labade, Heidi Kletzien, Alia Meliki, Andrew Castillo, Neva C Durand, Eugenio Mattei, Lauren J Anderson, Tristan Tay, Andrew S Earl, Noam Shoresh, Charles B Epstein, Amy J Wagers, Jason D Buenrostro.
      Cis-regulatory elements (CREs) control gene expression and are dynamic in their structure and function, reflecting changes in the composition of diverse effector proteins over time1. However, methods for measuring the organization of effector proteins at CREs across the genome are limited, hampering efforts to connect CRE structure to their function in cell fate and disease. Here we developed PRINT, a computational method that identifies footprints of DNA-protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size. Using these multiscale footprints, we created the seq2PRINT framework, which uses deep learning to allow precise inference of transcription factor and nucleosome binding and interprets regulatory logic at CREs. Applying seq2PRINT to single-cell chromatin accessibility data from human bone marrow, we observe sequential establishment and widening of CREs centred on pioneer factors across haematopoiesis. We further discover age-associated alterations in the structure of CREs in murine haematopoietic stem cells, including widespread reduction of nucleosome footprints and gain of de novo identified Ets composite motifs. Collectively, we establish a method for obtaining rich insights into DNA-binding protein dynamics from chromatin accessibility data, and reveal the architecture of regulatory elements across differentiation and ageing.
    DOI:  https://doi.org/10.1038/s41586-024-08443-4
  8. Nat Cancer. 2025 Jan 20.
    Refining biomarker design in light of cancer evolution.
      
    DOI:  https://doi.org/10.1038/s43018-024-00884-0
  9. Nat Methods. 2025 Jan 23.
    Precision control of cellular functions with a temperature-sensitive protein.
      
    DOI:  https://doi.org/10.1038/s41592-024-02573-3
  10. Cancer Res. 2025 Jan 22.
    SMAD4 and KRAS Status Shape Cancer Cell-Stromal Crosstalk and Therapeutic Response in Pancreatic Cancer.
    Eloise G Lloyd, Muntadher Jihad, Judhell S Manansala, Wenlong Li, Priscilla S W Cheng, Gianluca Mucciolo, Marta Zaccaria, Sara Pinto Teles, Joaquín Araos Henríquez, Sneha Harish, Rebecca Brais, Sally Ashworth, Weike Luo, Paul M Johnson, Lisa Veghini, Mireia Vallespinos, Vincenzo Corbo, Giulia Biffi.
      Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on pre-clinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase understanding of malignant cell-stroma crosstalk in PDAC. Here, we used single-cell RNA-sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V in which Smad4 was wild-type or deleted. KrasG12D Smad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared to KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype impacts cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2330
  11. Nature. 2025 Jan 22.
    Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted.
    Miguel Reina-Campos, Alexander Monell, Amir Ferry, Vida Luna, Kitty P Cheung, Giovanni Galletti, Nicole E Scharping, Kennidy K Takehara, Sara Quon, Peter P Challita, Brigid Boland, Yun Hsuan Lin, William H Wong, Cynthia S Indralingam, Hayley Neadeau, Suzie Alarcón, Gene W Yeo, John T Chang, Maximilian Heeg, Ananda W Goldrath.
      Tissue-resident memory CD8 T (TRM) cells provide protection from infection at barrier sites. In the small intestine, TRM cells are found in at least two distinct subpopulations: one with higher expression of effector molecules and another with greater memory potential1. However, the origins of this diversity remain unknown. Here we proposed that distinct tissue niches drive the phenotypic heterogeneity of TRM cells. To test this, we leveraged spatial transcriptomics of human samples, a mouse model of acute systemic viral infection and a newly established strategy for pooled optically encoded gene perturbations to profile the locations, interactions and transcriptomes of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. Our study reveals that the regionalized signalling of the intestinal architecture supports two distinct TRM cell states: differentiated TRM cells and progenitor-like TRM cells, located in the upper villus and lower villus, respectively. This diversity is mediated by distinct ligand-receptor activities, cytokine gradients and specialized cellular contacts. Blocking TGFβ or CXCL9 and CXCL10 sensing by antigen-specific CD8 T cells revealed a model consistent with anatomically delineated, early fate specification. Ultimately, our framework for the study of tissue immune networks reveals that T cell location and functional state are fundamentally intertwined.
    DOI:  https://doi.org/10.1038/s41586-024-08466-x
  12. Genome Med. 2025 Jan 17. 17(1): 5
    Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer.
    Luis Aparicio, Laura Crowley, John R Christin, Caroline J Laplaca, Hanina Hibshoosh, Raul Rabadan, Michael M Shen.
       BACKGROUND: Despite extensive analysis, the dynamic changes in prostate epithelial cell states during tissue homeostasis as well as tumor initiation and progression have been poorly characterized. However, recent advances in single-cell RNA-sequencing (scRNA-seq) technology have greatly facilitated studies of cell states and plasticity in tissue maintenance and cancer, including in the prostate.
    METHODS: We have performed meta-analyses of new and previously published scRNA-seq datasets for mouse and human prostate tissues to identify and compare cell populations across datasets in a uniform manner. Using random matrix theory to denoise datasets, we have established reference cell type classifications for the normal mouse and human prostate and have used optimal transport to compare the cross-species transcriptomic similarities of epithelial cell populations. In addition, we have integrated analyses of single-cell transcriptomic states with copy number variants to elucidate transcriptional programs in epithelial cells during human prostate cancer progression.
    RESULTS: Our analyses demonstrate transcriptomic similarities between epithelial cell states in the normal prostate, in the regressed prostate after androgen-deprivation, and in primary prostate tumors. During regression in the mouse prostate, all epithelial cells shift their expression profiles toward a proximal periurethral (PrU) state, demonstrating an androgen-dependent plasticity that is restored to normal during androgen restoration and gland regeneration. In the human prostate, we find substantial rewiring of transcriptional programs across epithelial cell types in benign prostate hyperplasia and treatment-naïve prostate cancer. Notably, we detect copy number variants predominantly within luminal acinar cells in prostate tumors, suggesting a bias in their cell type of origin, as well as a larger field of transcriptomic alterations in non-tumor cells. Finally, we observe that luminal acinar tumor cells in treatment-naïve prostate cancer display heterogeneous androgen receptor (AR) signaling activity, including a split between AR-positive and AR-low profiles with similarity to PrU-like states.
    CONCLUSIONS: Taken together, our analyses of cellular heterogeneity and plasticity provide important translational insights into the origin and treatment response of prostate cancer. In particular, the identification of AR-low tumor populations suggests that castration-resistance and predisposition to neuroendocrine differentiation may be pre-existing properties in treatment-naïve primary tumors that are selected for by androgen-deprivation therapies.
    Keywords:  Androgen receptor; Castration; Field cancerization; Plasticity; Prostate cancer; ScRNA-seq; Tumor heterogeneity
    DOI:  https://doi.org/10.1186/s13073-025-01432-w
  13. Cell. 2025 Jan 12. pii: S0092-8674(24)01425-9. [Epub ahead of print]
    Spatiotemporal and genetic cell lineage tracing of endodermal organogenesis at single-cell resolution.
    Ke-Ran Li, Pei-Long Yu, Qi-Qi Zheng, Xin Wang, Xuan Fang, Lin-Chen Li, Cheng-Ran Xu.
      During early mammalian development, the endoderm germ layer forms the foundation of the respiratory and digestive systems through complex patterning. This intricate process, guided by a series of cell fate decisions, remains only partially understood. Our study introduces innovative genetic tracing codes for 14 distinct endodermal regions using novel mouse strains. By integrating high-throughput and high-precision single-cell RNA sequencing with sophisticated imaging, we detailed the spatiotemporal and genetic lineage differentiation of the endoderm at single-cell resolution. We discovered an unexpected multipotentiality within early endodermal regions, allowing differentiation into various organ primordia. This research illuminates the complex and underestimated phenomenon where endodermal organs develop from multiple origins, prompting a reevaluation of traditional differentiation models. Our findings advance understanding in developmental biology and have significant implications for regenerative medicine and the development of advanced organoid models, providing insights into the intricate mechanisms that guide organogenesis.
    Keywords:  cellular differentiation; five-dimensional cell lineage tracing; genetic lineage tracing; mouse endodermal organogenesis; multi-origin organs; single-cell RNA sequencing; spatiotemporal analysis
    DOI:  https://doi.org/10.1016/j.cell.2024.12.012
  14. BMC Biol. 2025 Jan 23. 23(1): 23
    Consensus representation of multiple cell-cell graphs from gene signaling pathways for cell type annotation.
    Yu-An Huang, Yue-Chao Li, Zhu-Hong You, Lun Hu, Peng-Wei Hu, Lei Wang, Yuzhong Peng, Zhi-An Huang.
       BACKGROUND: Recent advancements in single-cell RNA sequencing have greatly expanded our knowledge of the heterogeneous nature of tissues. However, robust and accurate cell type annotation continues to be a major challenge, hindered by issues such as marker specificity, batch effects, and a lack of comprehensive spatial and interaction data. Traditional annotation methods often fail to adequately address the complexity of cellular interactions and gene regulatory networks.
    RESULTS: We proposed scMCGraph, a comprehensive computational framework that integrates gene expression with pathway activity to accurately annotate cell types within diverse scRNA-seq datasets. Initially, our model constructs multiple pathway-specific views using various pathway databases, which reflect both gene expression and pathway activities. These pathway-specific views are then integrated into a consensus graph. The consensus graph is subsequently utilized to reconstruct the multiple pathway views. Our model demonstrated exceptional robustness and accuracy across various analyses, including cross-platform, cross-time, cross-sample, and clinical dataset evaluations.
    CONCLUSIONS: scMCGraph represents a significant advance in cell type annotation. The experiments have demonstrated that introducing pathway information significantly improves the learning of cell-cell graphs, with their resulting consensus graph enhancing the predictive performance of cell type prediction. Different pathway databases provide complementary data, and an increase in the number of pathways can also boost model performance. Extensive testing shows that in various cross-dataset application scenarios, scMCGraph consistently exhibits both accuracy and robustness.
    Keywords:  Cell type annotation; Cellular communication; Consensus graph; Pathway integration; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1186/s12915-025-02128-8
  15. Nat Rev Mol Cell Biol. 2025 Jan 20.
    Sequencing technologies to measure translation in single cells.
    Michael VanInsberghe, Alexander van Oudenaarden.
      Translation is one of the most energy-intensive processes in a cell and, accordingly, is tightly regulated. Genome-wide methods to measure translation and the translatome and to study the complex regulation of protein synthesis have enabled unprecedented characterization of this crucial step of gene expression. However, technological limitations have hampered our understanding of translation control in multicellular tissues, rare cell types and dynamic cellular processes. Recent optimizations, adaptations and new techniques have enabled these measurements to be made at single-cell resolution. In this Progress, we discuss single-cell sequencing technologies to measure translation, including ribosome profiling, ribosome affinity purification and spatial translatome methods.
    DOI:  https://doi.org/10.1038/s41580-024-00822-z
  16. Cell Genom. 2025 Jan 16. pii: S2666-979X(24)00373-2. [Epub ahead of print] 100744
    Single-cell DNA sequencing reveals pervasive positive selection throughout preleukemic evolution.
    Gladys Poon, Aditi Vedi, Mathijs Sanders, Elisa Laurenti, Peter Valk, Jamie R Blundell.
      The representation of driver mutations in preleukemic hematopoietic stem cells (pHSCs) provides a window into the somatic evolution that precedes acute myeloid leukemia (AML). Here, we isolate pHSCs from the bone marrow of 16 patients diagnosed with AML and perform single-cell DNA sequencing on thousands of cells to reconstruct phylogenetic trees of the major driver clones in each patient. We develop a computational framework that can infer levels of positive selection operating during preleukemic evolution from the statistical properties of these phylogenetic trees. Combining these data with 67 previously published phylogenetic trees, we find that the highly variable structures of preleukemic trees emerge naturally from a simple model of somatic evolution with pervasive positive selection typically in the range of 9%-24% per year. At these levels of positive selection, we show that the identification of early multiple-mutant clones could be used to identify individuals at risk of future AML.
    Keywords:  acute myeloid leukemia; cancer evolution; clonal hematopoiesis; early detection; evolutionary dynamics; pre-cancer; somatic mutation
    DOI:  https://doi.org/10.1016/j.xgen.2024.100744
  17. Nature. 2025 Jan 17.
    How to trick the immune system into attacking tumours.
    Saima Sidik.
      
    Keywords:  CRISPR-Cas9 genome editing; Cancer; Medical research; Virology
    DOI:  https://doi.org/10.1038/d41586-025-00126-y
  18. Cancer Cell. 2025 Jan 13. pii: S1535-6108(24)00483-5. [Epub ahead of print]
    A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer.
    Amelia Acha-Sagredo, Pietro Andrei, Kalum Clayton, Emma Taggart, Carlotta Antoniotti, Chloé A Woodman, Hassnae Afrache, Constance Fourny, Maria Armero, Hafsa Kaja Moinudeen, Mary Green, Nisha Bhardwaj, Anna Mikolajczak, Maria Rodriguez-Lopez, Marg Crawford, Emma Connick, Steven Lim, Philip Hobson, Josep Linares, Ekaterina Ignatova, Diana Pelka, Elizabeth C Smyth, Nikolaos Diamantis, Dominika Sosnowska, Martina Carullo, Paolo Ciraci, Francesca Bergamo, Rossana Intini, Emma Nye, Patricia Barral, Michele Mishto, James N Arnold, Sara Lonardi, Chiara Cremolini, Elisa Fontana, Manuel Rodriguez-Justo, Francesca D Ciccarelli.
      Fewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI). Identifying and expanding this patient population remains a pressing clinical need. Here, we report that an interferon-high immunophenotype locally enriched in cytotoxic lymphocytes and antigen-presenting macrophages is required for response. This immunophenotype is not exclusive to dMMR CRCs but comprises a subset of MMR proficient (pMMR) CRCs. Single-cell spatial analysis and in vitro cell co-cultures indicate that interferon-producing cytotoxic T cells induce overexpression of antigen presentation in adjacent macrophages and tumor cells, including MHC class II invariant chain CD74. dMMR CRCs expressing high levels of CD74 respond to ICI and a subset of CD74 high pMMR CRC patients show better progression free survival when treated with ICI. Therefore, CD74 abundance can identify the constitutive interferon-high immunophenotype determining clinical benefit in CRC, independently of tumor mutational burden or MMR status.
    Keywords:  CD74; antigen presentation; colorectal cancer; immunotherapy; interferon; marker of response; patient stratification; spatial transcriptomics; tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2024.12.008
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