bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–05–25
nine papers selected by
Xiao Qin, University of Oxford
  1. Curating a single-cell data atlas for a deeper understanding of intra-tumor heterogeneity.
  2. Phenotypic heterogeneity and plasticity in colorectal cancer metastasis.
  3. Tumour plasticity and immune dynamics promote resistance to neo-adjuvant treatment.
  4. HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury.
  5. Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment.
  6. Beyond cell atlases: spatial biology reveals mechanisms behind disease.
  7. Powerful CRISPR system inserts whole gene into human DNA.
  8. Use of Large Language Models in Clinical Cancer Research.
  9. In vivo CAR engineering for immunotherapy.
  1. Nat Cancer. 2025 May 22.
    Curating a single-cell data atlas for a deeper understanding of intra-tumor heterogeneity.
      
    DOI:  https://doi.org/10.1038/s43018-025-00956-9
  2. Cell Genom. 2025 May 15. pii: S2666-979X(25)00137-5. [Epub ahead of print] 100881
    Phenotypic heterogeneity and plasticity in colorectal cancer metastasis.
    Cancer Tissue Bank
      Phenotypic heterogeneity and plasticity in colorectal cancer (CRC) has a crucial role in tumor progression, metastasis, and therapy resistance. However, the regulatory factors and the extrinsic signals driving phenotypic heterogeneity remain unknown. Using a combination of single-cell multiomics and spatial transcriptomics data from primary and metastatic CRC patients, we reveal cancer cell states with regenerative and inflammatory phenotypes that closely resemble metastasis-initiating cells in mouse models. We identify an intermediate population with a hybrid regenerative and stem phenotype. We reveal the transcription factors AP-1 and nuclear factor κB (NF-κB) as their key regulators and show localization of these states in an immunosuppressive niche both at the invasive edge in primary CRC and in liver metastasis. We uncover ligand-receptor interactions predicted to activate the regenerative and inflammatory phenotype in cancer cells. Together, our findings reveal regulatory and signaling factors that mediate distinct cancer cell states and can serve as potential targets to impair metastasis.
    Keywords:  AP-1; NOTUM; colorectal cancer; metastasis; phenotypic heterogeneity; plasticity; single-cell multiomics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.xgen.2025.100881
  3. Nat Cancer. 2025 May 22.
    Tumour plasticity and immune dynamics promote resistance to neo-adjuvant treatment.
      
    DOI:  https://doi.org/10.1038/s43018-025-00954-x
  4. Cell Stem Cell. 2025 May 19. pii: S1934-5909(25)00177-8. [Epub ahead of print]
    HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury.
    Wei-Chien Yuan, Andrew S Earl, Sai Ma, Karel Alcedo, Jacquelyn O Russell, Fabiana M Duarte, Yen-Ting Chu, Pei-Chi Chang, Hsin-Yi Chen, Hsin-Hui Chi, Qian Zhu, Alejo E Rodriguez-Fraticelli, Sachin H Patel, Yu-Ru Lee, Jason D Buenrostro, Fernando D Camargo.
      Hepatocytes can reprogram into biliary epithelial cells (BECs) during liver injury, but the underlying epigenetic mechanisms remain poorly understood. Here, we define the chromatin dynamics of this process using single-cell ATAC-seq and identify YAP/TEAD activation as a key driver of chromatin remodeling. An in vivo CRISPR screen highlights the histone acetyltransferase HBO1 as a critical barrier to reprogramming. HBO1 is recruited by YAP to target loci, where it promotes histone H3 lysine 14 acetylation (H3K14ac) and engages the chromatin reader zinc-finger MYND-type containing 8 (ZMYND8) to suppress YAP/TEAD-driven transcription. Loss of HBO1 accelerates chromatin remodeling, enhances YAP binding, and enables a more complete hepatocyte-to-BEC transition. Our findings position HBO1 as an epigenetic brake that restrains YAP-mediated reprogramming, suggesting that targeting HBO1 may enhance hepatocyte plasticity for liver regeneration.
    Keywords:  HBO1; Hippo-YAP; epigenetic regulation; hepatocyte reprogramming; in vivo CRISPR screen
    DOI:  https://doi.org/10.1016/j.stem.2025.04.010
  5. Trends Cancer. 2025 May 16. pii: S2405-8033(25)00112-8. [Epub ahead of print]
    Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment.
    Norihiro Goto, Judith Agudo, Ömer H Yilmaz.
      Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.
    Keywords:  colorectal cancer; immune evasion; niche cell; stem cell
    DOI:  https://doi.org/10.1016/j.trecan.2025.04.016
  6. Nat Biotechnol. 2025 May 21.
    Beyond cell atlases: spatial biology reveals mechanisms behind disease.
    Caroline Seydel.
      
    DOI:  https://doi.org/10.1038/s41587-025-02699-5
  7. Nature. 2025 May 15.
    Powerful CRISPR system inserts whole gene into human DNA.
    Elie Dolgin.
      
    Keywords:  CRISPR-Cas9 genome editing; Gene therapy; Microbiology
    DOI:  https://doi.org/10.1038/d41586-025-01518-w
  8. JCO Clin Cancer Inform. 2025 May;9 e2500027
    Use of Large Language Models in Clinical Cancer Research.
    Kenneth L Kehl.
      Artificial intelligence (AI) is increasingly being applied to clinical cancer research, driving precision oncology objectives by gathering clinical data at scales that were not previously possible. Although small, domain-specific models have been used toward this end for several years, general-purpose large language models (LLMs) now enable scalable data extraction and analysis without the need for large, labeled training data sets. These models support several applications, including building clinico-omic databases, matching patients to clinical trials, and developing multimodal foundation models that integrate text, imaging, and molecular data. LLMs can also streamline research workflows, from automating documentation to accelerating clinical decision making. However, data privacy, hallucination risks, computational costs, regulatory requirements, and validation standards remain significant considerations. Careful implementation of AI tools will therefore be an important task for cancer researchers in coming years.
    DOI:  https://doi.org/10.1200/CCI-25-00027
  9. Nat Rev Immunol. 2025 May 16.
    In vivo CAR engineering for immunotherapy.
    Yan-Ruide Li, Yichen Zhu, Tyler Halladay, Lili Yang.
      Chimeric antigen receptor (CAR)-engineered immune cell therapy represents an important advance in cancer treatments. However, the complex ex vivo cell manufacturing process and stringent patient selection criteria curtail its widespread use. In vivo CAR engineering is emerging as a promising off-the-shelf therapy, providing advantages such as streamlined production, elimination of patient-specific manufacturing, reduced costs and simplified logistics. A large set of preclinical findings has inspired further investigation into treatments for hard-to-treat diseases such as solid tumours and has facilitated the development of advanced products to enhance in vivo CAR engineering efficacy, the persistence of the cellular therapeutic and safety. In this Review, we summarize current in vivo CAR engineering strategies, including nanoparticle-based and viral delivery systems as well as bioinstructive implantable scaffolds, and discuss their advantages and disadvantages. Additionally, we provide a systematic comparison between in vivo and conventional ex vivo CAR engineering methods and address the challenges and future prospects of in vivo CAR engineering.
    DOI:  https://doi.org/10.1038/s41577-025-01174-1
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