bims-enbcad 2025-11-16 papers

Issue of 2025–11–16
seven papers selected by
Xiao Qin, University of Oxford

Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2514643122

METTL3-dependent m6A RNA methylation suppresses aberrant mammary epithelial differentiation and neoplastic transformation.

The mechanisms underlying sustained proliferation and aberrant cellular plasticity that drive early breast tumorigenesis remain unclear. Using CRISPR knockout (KO) screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of METTL3 stimulates mammary epithelial proliferation and reprograms gene expression in an m6A methyltransferase-dependent manner. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanistically, METTL3 loss reduces RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulation of interferon-STAT signaling. This inflammatory response leads to cross talk between STAT and GATA3 transcription factors, resulting in transcriptional activation of luminal genes in the mammary epithelium. These findings identify a cell-intrinsic epigenetic loop contributing to mammary epithelial differentiation and highlight a potential role of loss of METTL3-dependent m6A modification during neoplastic transformation.

Keywords: RNA methylation; breast cancer; epitranscriptomics; mammary development; transposable elements

DOI: https://doi.org/10.1073/pnas.2514643122

Nature. 2025 Nov;647(8089): S8-S11

Is ageing a disease? The debate that could reshape medicine.

Rachel Nuwer.

Keywords: Ageing; Alzheimer's disease; Research data

DOI: https://doi.org/10.1038/d41586-025-03525-3

Eur J Immunol. 2025 Nov;55(11): e70094

Spatial Immunometabolism: Integrating Technologies to Decode Cellular Metabolism in Tissues.

Felix J Hartmann.

The metabolic programs of immune cells influence their activation, differentiation, and effector functions. While much of immunometabolism has focused on cell-intrinsic regulation, it is now clear that metabolic activity is profoundly influenced by the surrounding tissue environment. In tumors and other inflammatory settings, immune cells are shaped by nutrient gradients, hypoxia, and immunoregulatory metabolites, factors that are spatially heterogeneous and often poorly captured by traditional methods. This review highlights recent technological advances that enable spatially resolved analysis of immune metabolism, with an emphasis on multimodal integration and cancer as a model system. Mass spectrometry imaging (MALDI, DESI), high-resolution platforms like SIMS, and vibrational imaging approaches such as Raman microscopy enable direct visualization of metabolites in tissue. Transcriptomic and proteomic data can be used to infer metabolic states, and computational models are being developed to integrate these diverse data layers. Together, these technologies are transforming the study of immunometabolism from dissociated cells to the intact tissue context. Key challenges remain in resolution, annotation, and data integration, but spatial immunometabolism holds particular promise for illuminating mechanisms of immune regulation in health and disease.

Keywords: antitumor immunity; cellular metabolism; immunometabolism; multiplexed imaging; spatial biology; systems immunology; tumor microenvironment

DOI: https://doi.org/10.1002/eji.70094

Cancer Heterog Plast. 2025 ;2(4):

Advancing Cancer Biology: Highlights from the 2025 FASEB SRC on Cellular Plasticity in Cancer.

Hans Clevers, Ankur Sharma, Sendurai A Mani, Anna Golebiewska, Axel Behrens, Wai Leong Tam, Loic P Deleyrolle, Huiping Liu, Karuna Ganesh, Walid T Khaled, Shaheen Sikandar, Terence K Lee, Tyler E Miller, Dean G Tang, Sheila Singh, Vivian S W Li, Justin D Lathia, Stephanie Ma.

The inaugural FASEB Science Research Conference (SRC) on Cellular Plasticity in Cancer was held in May 2025 in Hong Kong SAR, China. This event brought together leading experts to discuss cutting-edge research centered on cancer cell plasticity. The conference featured comprehensive presentations covering a broad spectrum of topics, including oncofetal reprogramming in tumor development and progression, mechanisms regulating cancer cell plasticity, metabolic reprogramming and its role in tumor progression, cancer cell plasticity during metastasis, cancer stem cell programs within the tumor microenvironment, tumor plasticity and immune evasion, as well as innovative therapeutic strategies aimed at targeting stem cell-like states, modulating cancer cell states, and effectively controlling disease progression. It is anticipated that the insights gained from this meeting will catalyze further advancements in cancer biology and therapy.

Keywords: cancer cell plasticity; cancer stem cells; cellular plasticity; immune evasion; phenotypic switching; therapy resistance; tumor microenvironment

DOI: https://doi.org/10.47248/chp2502040018

Cell. 2025 Nov 13. pii: S0092-8674(25)01151-1. [Epub ahead of print]188(23): 6393-6410

Bridging single cells to organs: Mesoscale modules as fundamental units of tissue function.

Yun Chen, Ronald N Germain, Ginger L Hunter, Rajan P Kulkarni, Arthur D Lander, Pedro Lowenstein, Jeremy E Purvis, Harikesh S Wong.

Recent studies at molecular and genomic scales have enriched our understanding of life's most fundamental building block: the cell. However, bridging the gap between single-cell phenotypes and the emergent functions of tissues and organs remains a formidable challenge. Here, we suggest that the conceptual span from cells to tissues and organs is so large as to warrant intermediate stepping stones. Drawing inspiration from "network motifs"-discrete units of cell-level function that emerge from the interactions of a handful of genes or enzymes-we argue that similarly identifiable units of tissue-level function, which we term "mesoscale modules," emerge from coordinated "interactions" among relatively small numbers of cells and their extracellular milieu. We outline several such modules and propose that a concerted effort to study them will deepen our foundational understanding of tissue and organ functions. By developing these mesoscale insights, we anticipate a more tractable and mechanistic approach to complex human conditions rooted in tissue- and organ-scale dysregulation, including developmental defects, cancer, cardiovascular disease, immune-related disorders, infectious disease, and aging.

Keywords: emergent properties; mesoscale modules; network motifs; systems biology; tissue biology

DOI: https://doi.org/10.1016/j.cell.2025.10.012