bims-gerecp 2025-11-02 papers

bims-gerecp

Biomed News

on Gene regulatory networks of epithelial cell plasticity

Issue of 2025–11–02
eight papers selected by
Xiao Qin, University of Oxford

Improved reconstruction of single-cell developmental potential with CytoTRACE 2.
Transcription factor switching drives subtype-specific pancreatic cancer.
Fusobacterium, quiescent niches, and therapy response in colorectal cancer.
From mechanisms to precision medicine: the role of organoids in studying the gut microbiota-tumor microenvironment axis.
Transformative advances in single-cell omics: a comprehensive review of foundation models, multimodal integration and computational ecosystems.
Unveiling metabolic pathway dysregulation in the malignant transformation of polyps to colorectal cancer: a single-cell analysis of epithelial cell trajectories.
Oncogenic Ras activation in permissive somatic cells triggers rapid-onset phenotypic plasticity and elicits a tumor-promoting neutrophil response.
A single-chain derivative of an integrin-activating antibody potentiates organoid growth in Matrigel and collagen hydrogels.

Nat Methods. 2025 Oct 27.

Improved reconstruction of single-cell developmental potential with CytoTRACE 2.

Minji Kang, Gunsagar S Gulati, Erin L Brown, Zhen Qi, Susanna Avagyan, Jose Juan Almagro Armenteros, Rachel Gleyzer, Wubing Zhang, Chloé B Steen, Jeremy Philip D'Silva, Janella Schwab, Michael F Clarke, Aadel A Chaudhuri, Aaron M Newman.

While single-cell RNA sequencing has advanced our understanding of cell fate, identifying molecular hallmarks of potency-a cell's ability to differentiate into other cell types-remains a challenge. Here we introduce CytoTRACE 2, an interpretable deep learning framework for predicting absolute developmental potential from single-cell RNA sequencing data. Across diverse platforms and tissues, CytoTRACE 2 outperformed previous methods in predicting developmental hierarchies, enabling detailed mapping of single-cell differentiation landscapes and expanding insights into cell potency.

DOI: https://doi.org/10.1038/s41592-025-02857-2
Nat Genet. 2025 Oct 30.

Transcription factor switching drives subtype-specific pancreatic cancer.

Shalini V Rao, Lisa Young, Danya Cheeseman, Sean Flynn, Niklas Krebs, Dominique-Laurent Couturier, Stephanie Mack, Rebecca Brais, Jill Temple, Amy Smith, Evangelia Papachristou, Catarina Pelicano, Chandra Sekhar Reddy Chilamakuri, Krzysztof Herka, Hideo Baba, Luay Farah, Phyllis F Cheung, Jens Siveke, Stéphane Guerrier, Luca Insolia, Michael Gill, Emily Archer Goode, Steven Kupczak, Yi Cheng, Giacomo Borsari, Duncan Jodrell, Clive D'Santos, Alasdair Russell, Barbara T Grünwald, Eva Serrao, Igor Chernukhin, Jason S Carroll.

Emerging evidence suggests that lineage-specifying transcription factors control the progression of pancreatic ductal adenocarcinoma (PDAC). We have discovered a transcription factor switching mechanism involving the poorly characterized orphan nuclear receptor HNF4G and the putative pioneer factor FOXA1, which drives PDAC progression. Using our unbiased protein interactome discovery approach, we identified HNF4A and HNF4G as reproducible, FOXA1-associated proteins, in both preclinical models and Whipple surgical samples. In the primary tumor context, we consistently find that the dominant transcription factor is HNF4G, where it functions as the driver. A molecular switch occurs in advanced disease, whereby HNF4G expression or activity decreases, unmasking FOXA1's transcriptional potential. Derepressed FOXA1 drives late-stage disease by orchestrating metastasis-specific enhancer-promoter loops to regulate the expression of metastatic genes. Overall survival is influenced by HNF4G and FOXA1 activity in primary tumor growth and in metastasis, respectively. We suggest that the existence of stage-dependent transcription factor activity, triggered by molecular compartmentalization, mediates the progression of PDAC.

DOI: https://doi.org/10.1038/s41588-025-02389-7
Cancer Cell. 2025 Oct 30. pii: S1535-6108(25)00443-X. [Epub ahead of print]

Fusobacterium, quiescent niches, and therapy response in colorectal cancer.

Bassel Ghaddar, Subhajyoti De, Martin J Blaser.

In this issue of Cancer Cell, Galeano Niño et al. report that tumor-infiltrating bacteria like Fusobacterium species induce a quiescent, chemoresistant state in cancer cells in the colon by disrupting epithelial contacts and suppressing proliferation and transcription. These studies highlight microbial-tumor interactions as potential modulators of therapeutic response in colon cancer.

DOI: https://doi.org/10.1016/j.ccell.2025.10.002
Front Microbiol. 2025 ;16 1669482

From mechanisms to precision medicine: the role of organoids in studying the gut microbiota-tumor microenvironment axis.

Si-Yang Zheng, You-Yu Su, Fu-Liang Cai, Da-Fang Xu, Yong-Qiang Xu.

  Intestinal organoids are three-dimensional in vitro models derived from patient-specific tissues, which can recapitulate the structural and functional characteristics of the native intestinal epithelium, including interactions with the gut microbiota. In the study of host-microbiota crosstalk within the context of the Tumor Microenvironment (TME), they have become highly effective tools, providing an opportunity to explore the role of microorganisms in carcinogenic processes, immune regulation, and therapeutic responses. Although organoids can successfully simulate key aspects of the TME, certain features-such as systemic immune interactions, neuroendocrine axes, and dynamic microbial communities-remain difficult to fully replicate. This review primarily covers the advances in organoids applied to the research of the microbiota-TME axis, examines their current limitations, and further advocates for their integration with multi-omics and organ-on-a-chip technologies to enhance physiological relevance and the value of translational applications.

Keywords:  gut microbiota; host–microbe interactions; microbial metabolites; organoids; tumor microenvironment

DOI:  https://doi.org/10.3389/fmicb.2025.1669482
J Transl Med. 2025 Oct 27. 23(1): 1176

Transformative advances in single-cell omics: a comprehensive review of foundation models, multimodal integration and computational ecosystems.

Taylor Yiu, Bin Chen, Haoyu Wang, Genyi Feng, Qiangqiang Fu, Huijing Hu.

  Recent advances in single-cell multi-omics technologies have revolutionized cellular analysis, enabling comprehensive exploration of cellular heterogeneity, developmental trajectories, and disease mechanisms at unprecedented resolution. Foundation models, originally developed for natural language processing, are now driving transformative approaches to high-dimensional, multimodal single-cell data analysis. Frameworks such as scGPT and scPlantFormer excel in cross-species cell annotation, in silico perturbation modeling, and gene regulatory network inference. Multimodal integration approaches, including pathology-aligned embeddings and tensor-based fusion, harmonize transcriptomic, epigenomic, proteomic, and spatial imaging data to delineate multilayered regulatory networks across biological scales. Federated computational platforms facilitate decentralized data analysis and standardized, reproducible workflows, fostering global collaboration. Challenges persist, including technical variability across platforms, limited model interpretability, and gaps in translating computational insights into clinical applications. Overcoming these hurdles demands standardized benchmarking, multimodal knowledge graphs, and collaborative frameworks that integrate artificial intelligence with human expertise. This review synthesizes recent technological advancements and proposes actionable strategies to bridge single-cell multi-omics innovations with mechanistic biology and precision medicine.

Keywords:  Cell type annotation; Computational ecosystems; Data harmonization; Foundation models; Multimodal integration; Perturbation modeling; Single-cell omics

DOI:  https://doi.org/10.1186/s12967-025-07091-0
Int J Surg. 2025 Oct 27.

Unveiling metabolic pathway dysregulation in the malignant transformation of polyps to colorectal cancer: a single-cell analysis of epithelial cell trajectories.

Hui Hu, Jianhong Wu, Yanjun Lu.

   BACKGROUND: Although metabolic reprogramming in colorectal cancer (CRC) has been studied, the changes in metabolic pathways and cellular communication from a healthy colon to precancerous adenoma and CRC remain poorly understood.
MATERIALS AND METHODS: Here, we utilized single-cell transcriptome data including normal, polyp, and tumor colon tissues to construct the epithelial cell differentiation trajectory during CRC progression. We scored pathway and lactylation activities using AUCell to analyze changes in CRC progression and the trajectory. We explored the cell communication between epithelial cells and other stromal cells during the process from polyps to CRC through cell communication analysis. Based on the transcription factor-gene-pathway regulatory network analysis, potential regulatory mechanisms were inferred.
RESULTS: We demonstrated that epithelial cell subpopulations dominate the malignant transformation process of CRC. The malignant trajectory of epithelial cell is accompanied by significant dysregulation of fatty acid and bile acid metabolism pathways, which may contribute to early CRC development. Additionally, this trajectory was associated with increased stemness, metastatic potential, and lactylation activity. The communication between Myofibroblasts/Endothelial and enterocytes subpopulations was established in the early CRC stages. Continuously altered genes (RUNX1, SOX4 STAT3, FOXO1) during CRC progression were closely related to metabolic regulations. Finally, seven dynamically changed lactylation-associated genes (HNRNPA1, PRPF6, PTMA, CALD1, FAM50A, RPL29, and RPL5) during CRC malignant transformation were identified as potential targets for metabolic intervention in CRC, highlighting a lactylation-related TF-gene-pathway regulatory network driving metabolic reprogramming.
CONCLUSION: This study elucidates the malignant evolution of epithelial cells, along with changes in metabolic pathway activity and key regulators, jointly promote CRC development. This research provides new insights into early CRC detection from the perspective of metabolic reprogramming, while nominating candidate targets worthy of further investigation for precise treatment strategies.

Keywords:  cellular communication; colorectal cancer; lactylation; malignant transformation; metabolism

DOI:  https://doi.org/10.1097/JS9.0000000000003859
Cell Rep. 2025 Oct 23. pii: S2211-1247(25)01249-5. [Epub ahead of print]44(11): 116478

Oncogenic Ras activation in permissive somatic cells triggers rapid-onset phenotypic plasticity and elicits a tumor-promoting neutrophil response.

Abigail M Elliot, Isabel Ribeiro Bravo, Yiyi Zhao, Zhuorui Wang, Jeanette Astorga Johansson, Esme Hutton, Richard Cunningham, Henna Myllymäki, Kai Yee Chang, Justyna Cholewa-Waclaw, Lisa Kelly, Mariana Beltran, Amy Lewis, Philip M Elks, Carsten Gram Hansen, Neil C Henderson, Yi Feng.

  Oncogenic driver mutations are common in normal tissues, indicating that non-genetic factors are necessary for tumorigenesis. Phenotypic plasticity is a crucial gateway to malignancy, and inflammation can fuel tumorigenesis; however, little is known about the timing and mechanisms by which these hallmarks first emerge. Using single-cell transcriptomics and in vivo live imaging, we characterized the immediate cell-intrinsic and innate immune responses during the first 24 h following oncogenic Ras activation in a zebrafish model of HRASG12V-mediated skin tumor initiation. We found that in a subset of basal keratinocytes, RAS alone drives phenotypic plasticity, and these cells undergo dedifferentiation and partial epithelial-to-mesenchymal transition (EMT), resembling malignant cells in human squamous cell carcinoma. Strikingly, these cells also drive a tumor-promoting neutrophil program, which in turn enhances preneoplastic cell proliferation. Thus, oncogenic Ras effects are dictated by the cell of origin, and we revealed a link between unlocking plasticity and the onset of tumor-promoting inflammation.

Keywords:  CP: Cancer; CP: Immunology; Ras; epithelial-mesenchymal transition; preneoplastic; tumor initiation; tumor-associated neutrophils; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2025.116478
Nat Biotechnol. 2025 Oct 28.

A single-chain derivative of an integrin-activating antibody potentiates organoid growth in Matrigel and collagen hydrogels.

Wim B M de Lau, Joost J A P M Wijnakker, Gijs J F van Son, Daniel Krueger, Daisong Wang, Matthijs S Abendroth, Robin Schreurs, Claudia Y Janda, Fenna L H van Rijt, Benjamin J P Chalopin, Emma Bokobza, Johan H van Es, Timothy A Springer, Arnoud Sonnenberg, Hans Clevers.

Current methods of culturing human epithelial organoids from adult stem cells may not be compatible with clinical applications as they rely on xenogeneic, chemically undefined or non-standardized components such as the basement membrane extract Matrigel. Matrigel provides a source of extracellular matrix molecules, including laminins and collagen IV, which interact with β1 integrins expressed on organoid cells. Here we describe a single-chain (sc) version of antibody TS2/16 that allosterically activates integrin β1 function in organoids. The addition of monomeric scTS2/16 to organoid medium results in up to a fivefold increase in the yield of all gastrointestinal organoids grown in Matrigel. Moreover, scTS2/16 supports a six- to sevenfold increase in the yield of these organoids when cultured in collagen I hydrogels, both in 3D and 2D. Collagen I is well defined, available in clinical-grade formulations and, when combined with scTS2/16, may support the clinical application of epithelial organoids derived from gastrointestinal tissues and other epithelial sources.

DOI: https://doi.org/10.1038/s41587-025-02874-8