bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–04–27
sixteen papers selected by
Xiao Qin, University of Oxford
  1. Four rising stars at the forefront of cancer research.
  2. In Vivo Reprogramming Highlights Epigenetic Regulation That Shapes Cancer Hallmarks.
  3. Transcriptome-wide analysis of differential expression in perturbation atlases.
  4. Joint analysis of chromatin accessibility and gene expression in the same single cells reveals cancer-specific regulatory programs.
  5. Single-cell Epigenomic Profiling with High-throughput Droplet scChIP-seq.
  6. Evolutionary paths towards metastasis.
  7. Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling.
  8. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer.
  9. How AI is helping to boost cancer screening.
  10. Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer.
  11. Which programming language should I use? A guide for early-career researchers.
  12. Tumor Spheroids, Tumor Organoids, Tumor Explants, and Tumoroids: What Are the Differences between Them?
  13. Cancer Stem Cells and Tumor-Associated Macrophages: Interactions and Therapeutic Opportunities.
  14. An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer.
  15. Plasticity of tumor cell immunogenicity: is it druggable?
  16. Proteomics of colorectal tumors identifies the role of CAVIN1 in tumor relapse.
  1. Nature. 2025 Apr;640(8060): S68-S71
    Four rising stars at the forefront of cancer research.
    Felicity Nelson, Sandy Ong.
      
    Keywords:  Cancer; Cell biology; Computational biology and bioinformatics; Drug discovery; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-01155-3
  2. Cancer Sci. 2025 Apr 21.
    In Vivo Reprogramming Highlights Epigenetic Regulation That Shapes Cancer Hallmarks.
    Yosuke Yamada, Nao Sankoda, Yasuhiro Yamada.
      Douglas Hanahan added "non-mutational epigenetic reprogramming" and "unlocking phenotypic plasticity" as new hallmarks of cancer, proposing that cancer cells possess fundamental features that are not directly linked to their genetic abnormalities. In vivo reprogramming studies have demonstrated that non-mutational epigenetic regulation can cause cellular reprogramming, leading to cancer development at the organismal level. Given that epigenetic regulation functions as an interface between the cellular environment and gene expression, these results suggest that intercellular communications in the tumor microenvironment play a critical role in cancer development. This review first introduces genetic aberrations that cause cancer development. Then, it illustrates the impact of epigenetic abnormalities in cancer, especially with reference to studies that use in vivo reprogramming technologies. Finally, it discusses the importance of histological evaluations of tumor tissue to understand non-cell-autonomous epigenetic regulation that establishes cancer hallmarks.
    Keywords:  cell dedifferentiation; hallmarks of cancer; in vivo reprogramming; non‐mutational epigenetic reprogramming; unlocking phenotypic plasticity
    DOI:  https://doi.org/10.1111/cas.70067
  3. Nat Genet. 2025 Apr 21.
    Transcriptome-wide analysis of differential expression in perturbation atlases.
    Ajay Nadig, Joseph M Replogle, Angela N Pogson, Mukundh Murthy, Steven A McCarroll, Jonathan S Weissman, Elise B Robinson, Luke J O'Connor.
      Single-cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are noisy, and many effects may go undetected. Here we introduce transcriptome-wide analysis of differential expression (TRADE)-a statistical model for the distribution of true differential expression effects that accounts for estimation error appropriately. TRADE estimates the 'transcriptome-wide impact', which quantifies the total effect of a perturbation across the transcriptome. Analyzing several large Perturb-seq datasets, we show that many transcriptional effects remain undetected in standard analyses but emerge in aggregate using TRADE. A typical gene perturbation affects an estimated 45 genes, whereas a typical essential gene affects over 500. We find moderate consistency of perturbation effects across cell types, identify perturbations where transcriptional responses vary qualitatively across dosage levels and clarify the relationship between genetic and transcriptomic correlations across neuropsychiatric disorders.
    DOI:  https://doi.org/10.1038/s41588-025-02169-3
  4. Cell Syst. 2025 Apr 15. pii: S2405-4712(25)00099-7. [Epub ahead of print] 101266
    Joint analysis of chromatin accessibility and gene expression in the same single cells reveals cancer-specific regulatory programs.
    Lei Tang, Jinsong Zhang, Yanqiu Shao, Yifan Wei, Yuzhe Li, Kang Tian, Xiang Yan, Changjiang Feng, Qiangfeng Cliff Zhang.
      Biological analyses conducted at the single-cell scale have revealed profound impacts of heterogeneity and plasticity of chromatin states and gene expression on physiology and cancer. Here, we developed Parallel-seq, a technology for simultaneously measuring chromatin accessibility and gene expression in the same single cells. By combining combinatorial cell indexing and droplet overloading, Parallel-seq generates high-quality data in an ultra-high-throughput fashion and at a cost two orders of magnitude lower than alternative technologies (10× Multiome and ISSAAC-seq). We applied Parallel-seq to 40 lung tumor and tumor-adjacent clinical samples and obtained over 200,000 high-quality joint scATAC-and-scRNA profiles. Leveraging this large dataset, we characterized copy-number variations (CNVs) and extrachromosomal circular DNA (eccDNA) heterogeneity in tumor cells, predicted hundreds of thousands of cell-type-specific regulatory events, and identified enhancer mutations affecting tumor progression. Our analyses highlight Parallel-seq's power in investigating epigenetic and genetic factors driving cancer development at the cell-type-specific level and its utility for revealing vulnerable therapeutic targets.
    Keywords:  epigenomics; gene expression regulation; lung cancer; single-cell multiomics
    DOI:  https://doi.org/10.1016/j.cels.2025.101266
  5. Methods Mol Biol. 2025 ;2919 213-239
    Single-cell Epigenomic Profiling with High-throughput Droplet scChIP-seq.
    Justine Marsolier, Eve Moutaux, Kevin Grosselin, Andrew Griffiths, Céline Vallot.
      Our high-throughput scChIP-seq approach combines droplet microfluidics with single-cell DNA barcoding to study the heterogeneity of epigenomes (H3K27me3, H3K4me3, H3K27Ac, H3K4me1) in a cellular population of several thousand cells with a coverage of up to 10,000 unique loci per cell.
    Keywords:  Chromatin; DNA barcoding; Droplet microfluidics; Epigenome profiling; Histone modifications
    DOI:  https://doi.org/10.1007/978-1-0716-4486-7_12
  6. Nat Rev Cancer. 2025 Apr 22.
    Evolutionary paths towards metastasis.
    Kamila Naxerova.
      The evolution of metastasis in humans is considerably less well understood than the biology of early carcinogenesis. For over a century, clinicians and scientists have been debating whether metastatic potential is the intrinsic property of a cancer, pre-determined by the molecular characteristics of the tumour founder cell, or whether metastatic capacity evolves in a stepwise fashion as the tumour grows, akin to the multistage accumulation of oncogenic alterations that give rise to the first cancer cell. In this Perspective, I examine how genetic analyses of primary tumours and matched metastases can distinguish between these two competing metastasis evolution models, with particular emphasis on the utility of metastatic randomness - a quantitative measure that reflects whether metastases arise from a random selection of primary tumour subclones or whether they are enriched for descendants of privileged lineages that have acquired pro-metastatic traits. Probable metastasis evolution trajectories in tumours with high and low baseline metastatic capacity are discussed, along with the role of seeding rates and selection at different metastatic host sites. Finally, I argue that trailblazing insights into human metastasis biology are immediately possible if we make a concerted effort to apply existing experimental and theoretical tools to the right patient cohorts.
    DOI:  https://doi.org/10.1038/s41568-025-00814-x
  7. Dev Cell. 2025 Apr 16. pii: S1534-5807(25)00177-7. [Epub ahead of print]
    Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling.
    Nicholas R Smith, Nicole R Giske, Sidharth K Sengupta, Patrick Conley, John R Swain, Ashvin Nair, Kathryn L Fowler, Christopher Klocke, Yeon Jung Yoo, Ashley N Anderson, Nasim Sanati, Kristof Torkenczy, Andrew C Adey, Jared M Fischer, Guanming Wu, Melissa H Wong.
      Intestinal epithelial development and homeostasis critically rely upon balanced stem cell proliferation, involving slow-cycling/label-retaining and active-cycling/canonical Wnt-dependent intestinal stem cell (ISC) subtypes. ISC regulation during development remains poorly understood but has important implications for establishing key mechanisms governing tissue maintenance. Herein, we identify Bmi1+ cells as functional stem cells present in early murine intestinal development, prior to Lgr5-expressing ISCs. Lineage tracing and single-cell RNA sequencing identify that Bmi1+ ISCs can trace to Lgr5+ ISCs and other differentiated lineages. Initially highly proliferative, Bmi1+ ISCs transition to slow-cycling states as Lgr5+ ISCs emerge. Non-canonical Wnt signaling regulates the proliferative Bmi1+ cell state. These findings highlight the dynamic interplay between stem cell populations and the opposing Wnt pathways that govern proliferation-ultimately having implications for tissue development, homeostasis, regeneration, and tumorigenesis. Understanding these fundamental developmental mechanisms is critical for understanding adult intestinal maintenance.
    Keywords:  Bmi1; Wnt signaling; development; intestinal stem cell
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.014
  8. Nature. 2025 Apr 23.
    Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer.
    Guangsheng Pei, Jimin Min, Kimal I Rajapakshe, Vittorio Branchi, Yunhe Liu, Benson Chellakkan Selvanesan, Fredrik Thege, Dorsay Sadeghian, Daiwei Zhang, Kyung Serk Cho, Yanshuo Chu, Enyu Dai, Guangchun Han, Mingyao Li, Cassian Yee, Kazuki Takahashi, Bharti Garg, Herve Tiriac, Vincent Bernard, Alexander Semaan, Jean L Grem, Thomas C Caffrey, Jared K Burks, Andrew M Lowy, Andrew J Aguirre, Paul M Grandgenett, Michael A Hollingsworth, Paola A Guerrero, Linghua Wang, Anirban Maitra.
      Patients with treatment-refractory pancreatic cancer often succumb to systemic metastases1-3; however, the transcriptomic heterogeneity that underlies therapeutic recalcitrance remains understudied, particularly in a spatial context. Here we construct high-resolution maps of lineage states, clonal architecture and the tumour microenvironment (TME) using spatially resolved transcriptomics from 55 samples of primary tumour and metastases (liver, lung and peritoneum) collected from rapid autopsies of 13 people. We observe discernible transcriptomic shifts in cancer-cell lineage states as tumours transition from primary sites to organ-specific metastases, with the most pronounced intra-patient distinctions between liver and lung. Phylogenetic trees constructed from inferred copy number variations in primary and metastatic loci in each patient highlight diverse patient-specific evolutionary trajectories and clonal dissemination. We show that multiple tumour lineage states co-exist in each tissue, including concurrent metastatic foci in the same organ. Agnostic to tissue site, lineage states correlate with distinct TME features, such as the spatial proximity of TGFB1-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) to aggressive 'basal-like' cancer cells, but not to cells in the 'classical' or 'intermediate' states. These findings were validated through orthogonal and cross-species analyses using mouse tissues and patient-derived organoids. Notably, basal-like cancer cells aligned with myCAFs correlate with plasma-cell exclusion from the tumour milieu, and neighbouring cell analyses suggest that CXCR4-CXCL12 signalling is the underlying basis for observed immune exclusion. Collectively, our findings underscore the profound transcriptomic heterogeneity and microenvironmental dynamics that characterize treatment-refractory pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41586-025-08927-x
  9. Nature. 2025 Apr;640(8060): S62-S64
    How AI is helping to boost cancer screening.
    Michael Eisenstein.
      
    Keywords:  Cancer; Health care; Machine learning; Medical research; Public health
    DOI:  https://doi.org/10.1038/d41586-025-01153-5
  10. Nat Immunol. 2025 Apr 22.
    Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer.
    Mojdeh Shakiba, David A Tuveson.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic 'cold' tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.
    DOI:  https://doi.org/10.1038/s41590-025-02134-6
  11. Nature. 2025 Apr;640(8060): 1116-1117
    Which programming language should I use? A guide for early-career researchers.
    Jeffrey M Perkel.
      
    Keywords:  Computational biology and bioinformatics; Computer science; Software; Technology
    DOI:  https://doi.org/10.1038/d41586-025-01241-6
  12. Biochemistry (Mosc). 2025 Feb;90(2): 200-213
    Tumor Spheroids, Tumor Organoids, Tumor Explants, and Tumoroids: What Are the Differences between Them?
    Mikhail Durymanov.
      Three-dimensional (3D) cell cultures that mimic tumor microenvironment have become an essential tool in cancer research and drug response analysis, significantly enhancing our understanding of tumor biology and advancing personalized medicine. Currently, the most widely mentioned 3D multicellular culture models include spheroids, organoids, tumor explants, and tumoroids. These 3D structures, exploited for various applications, are generated from cancer and non-cancer cells of different origin using multiple techniques. However, despite extensive research and numerous studies, consistent definitions of these 3D culture models are not clearly established. The manuscript provides a comprehensive overview of these models, detailing brief history of their research, unique biological characteristics, advantages, limitations, and specific applications.
    Keywords:  personalized medicine; tumor explants; tumor organoids; tumor spheroids; tumoroids
    DOI:  https://doi.org/10.1134/S0006297924604234
  13. Cancer Lett. 2025 Apr 22. pii: S0304-3835(25)00303-9. [Epub ahead of print] 217737
    Cancer Stem Cells and Tumor-Associated Macrophages: Interactions and Therapeutic Opportunities.
    Haitao Yuan, Yun Qiu, Zijie Mei, Jiaqing Liu, Lingna Wang, Kaiqing Zhang, Huicong Liu, Fangfang Zhu.
      Cancer stem cells (CSCs) depend on the tumor microenvironment (TME) to sustain their stem-like properties by recruiting monocytes and reprogramming them into tumor-associated macrophages (TAMs), which in turn promote tumor progression. This review explores CSC-TAM interactions, emphasizing how CSCs drive monocyte recruitment and TAM polarization. We discuss how TAMs enhance CSC stemness and niche maintenance through chemokines, cytokines, exosome-mediated miRNA transfer, direct interactions, and extracellular matrix (ECM) remodeling. Furthermore, we examine therapeutic strategies targeting TAMs, including inhibiting TAM differentiation, reprogramming TAM polarization, and leveraging immune checkpoint blockade and CAR-macrophage immunotherapy to improve cancer treatment outcomes.
    Keywords:  CAR-macrophage therapy; Cancer stem cells; Cancer stemness maintenance; Chemokine/cytokine signaling; Exosomal miRNAs; Immune checkpoint blockade; Macrophage polarization; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.canlet.2025.217737
  14. Nat Nanotechnol. 2025 Apr 23.
    An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer.
    Kai Zhao, Yu Yan, Xiao-Kang Jin, Ting Pan, Shi-Man Zhang, Chi-Hui Yang, Zhi-Yong Rao, Xian-Zheng Zhang.
      Chemoresistance and immunosuppression are common obstacles to the efficacy of chemo-immunotherapy in colorectal cancer (CRC) and are regulated by mitochondrial chaperone proteins. Here we show that the disruption of the tumour necrosis factor receptor-associated protein 1 (TRAP1) gene, which encodes a mitochondrial chaperone in tumour cells, causes the translocation of cyclophilin D in tumour cells. This process results in the continuous opening of the mitochondrial permeability transition pore, which enhances chemotherapy-induced cell necrosis and promotes immune responses. On the basis of this discovery we developed an oral CRISPR-Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes that disrupts the TRAP1 gene in CRC. This system penetrates the intestinal mucus layer and undergoes epithelial transcytosis, accumulating in CRC tissues. It enhances chemotherapeutic efficacy by overcoming chemoresistance and activating the tumour immune microenvironment in orthotopic, chemoresistant and spontaneous CRC models, with remarkable synergistic antitumour effects. This oral CRISPR-Cas9 delivery system represents a promising therapeutic strategy for the clinical management of CRC.
    DOI:  https://doi.org/10.1038/s41565-025-01904-5
  15. J Immunother Cancer. 2025 Apr 23. pii: e011859. [Epub ahead of print]13(4):
    Plasticity of tumor cell immunogenicity: is it druggable?
    Glenn Dranoff.
      This short perspective presents, at a high level, some observations and speculations about cancer immunotherapy that derive from experiences at the Dana-Farber Cancer Institute and the Novartis Institutes of Biomedical Research.
    Keywords:  Escape/evasion; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2025-011859
  16. Mol Syst Biol. 2025 Apr 23.
    Proteomics of colorectal tumors identifies the role of CAVIN1 in tumor relapse.
    Ana Martinez-Val, Leander Van der Hoeven, Dorte B Bekker-Jensen, Margarita Melnikova Jørgensen, Jesper Nors, Giulia Franciosa, Claus L Andersen, Jesper B Bramsen, Jesper V Olsen.
      Colorectal cancer molecular signatures derived from omics data can be employed to stratify CRC patients and aid decisions about therapies or evaluate prognostic outcome. However, molecular biomarkers for identification of patients at increased risk of disease relapse are currently lacking. Here, we present a comprehensive multi-omics analysis of a Danish colorectal cancer tumor cohort composed of 412 biopsies from tumors of 371 patients diagnosed at TNM stage II or III. From mass spectrometry-based patient proteome profiles, we classified the tumors into four molecular subtypes, including a mesenchymal-like subtype. As the mesenchymal-rich tumors are known to represent the most invasive and metastatic phenotype, we focused on the protein signature defining this subtype to evaluate their potential as relapse risk markers. Among signature-specific proteins, we followed-up Caveolae-Associated Protein-1 (CAVIN1) and demonstrated its role in tumor progression in a 3D in vitro model of colorectal cancer. Compared to previous omics analyses of CRC, our multi-omics classification provided deeper insights into EMT in cancer cells with stronger correlations with risk of relapse.
    Keywords:  CAVIN1; Colorectal Cancer; Proteomics; Tumor Relapse
    DOI:  https://doi.org/10.1038/s44320-025-00102-8
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