bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–01–04
thirteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU



  1. iScience. 2025 Dec 19. 28(12): 114204
      The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a sensor of growth signals that control cell growth, has been studied mainly in proliferating cells. Primary cilia are sensory organelles present on most quiescent cells and are essential for receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences primary cilia growth. Here, we show that mTORC1 promotes cilia elongation without affecting ciliogenesis by suppressing autophagy. Inhibiting mTORC1 through pharmacological, nutritional, or genetic interventions shortened primary cilia, whereas activation of the pathway elongated them. Furthermore, pharmacological or genetic inhibition of autophagy-a key downstream process blocked by mTORC1-elongated primary cilia and rendered them resistant to mTORC1 inhibition. These mTORC1-mediated effects extend to mouse neurons ex vivo and in vivo. Thus, the mTORC1-mediated regulation of autophagy controls primary cilia length and may contribute to diseases in which ciliary function is altered, referred to as ciliopathies.
    Keywords:  Cell biology; Molecular physiology
    DOI:  https://doi.org/10.1016/j.isci.2025.114204
  2. Methods Mol Biol. 2026 ;2989 31-50
      Cell Painting (CP) is a widely used imaging-based method for untargeted high-throughput phenotypic profiling (HTPP) of compounds or genetic perturbations that lead to morphological changes in cells. Here, we describe the Cell Painting PLUS (CPP) method, an efficient, robust, and broadly applicable HTPP approach that overcomes certain boundaries of the standard CP method. In CPP, an elution buffer enables iterative staining, elution, and re-staining of the same cells with at least seven fluorescent dyes labeling nine cellular compartments and organelles. In this way, CPP provides higher flexibility in selecting and combining various fluorescent dyes for customized multiplexing of phenotypic profiling screens. The separate imaging and analysis of single dyes in individual channels ensures a high specificity of the generated phenotypic profiles and thus enables precise insights into cellular processes and dysfunction. This chapter describes the process of generating CPP phenotypic profiling data that is based on automated staining and imaging procedures as well as a customized image analysis pipeline using the Harmony software. The resulting data can be further processed and visualized using customized KNIME software-based pipelines as described in von Coburg et al. (Nat Commun 16:3857, 2025) for unbiased and in-depth characterization of the modes-of-action of compounds or genetic perturbations in toxicology and biomedical research.
    Keywords:  Cell Painting PLUS; Harmony software; High-content screening; High-throughput; Morphological fingerprints; Phenotypic profiling
    DOI:  https://doi.org/10.1007/978-1-0716-4985-5_2
  3. J Cell Biol. 2026 Feb 02. pii: e202508058. [Epub ahead of print]225(2):
      Molecular biology has benefited enormously from repurposed tools-many enzymes and antibodies evolved for other functions but are now essential for interrogating biological function by manipulating proteins or nucleic acids. In contrast, lipids have remained technically difficult to visualize or manipulate in cells. This review introduces tools that bring lipid biology into reach for molecular cell biologists, using familiar experimental approaches. We first describe adaptations of immunofluorescence and live-cell imaging of fluorescent molecules to track lipids. Then, we discuss tools for manipulating lipid levels, including pharmacologic inhibitors, synthetic biology platforms for inducible lipid generation or degradation, and optogenetic systems for precise temporal control. While some methods remain technically demanding, most tools are now broadly accessible. Our goal is to offer a practical framework for integrating lipid biology into mainstream cell biology experiments.
    DOI:  https://doi.org/10.1083/jcb.202508058
  4. Nat Rev Genet. 2026 Jan 02.
      Single-cell analyses have transitioned from descriptive atlasing towards inferring causal effects and mechanistic relationships that capture cellular logic. Technological advances and the growing scale of observational and interventional datasets have fuelled the development of machine learning methods aimed at identifying such dependencies and extrapolating perturbation effects. Here, we review and connect these approaches according to their modelling concepts (including representation learning, causal inference, mechanistic discovery, disentanglement and population tracing), underlying assumptions and downstream tasks. We propose a unifying ontology to guide practitioners in selecting the most suitable methods for a given biological question, with detailed technical descriptions provided in an online resource . Finally, we identify promising computational directions and underexplored data properties that could pave the way for future developments.
    DOI:  https://doi.org/10.1038/s41576-025-00920-4
  5. Methods Mol Biol. 2026 ;2989 125-150
      High-content image-based cytological profiling is a powerful strategy for studying the effects of chemical and genetic perturbations on the cell. Cytological profiling assays illuminate multiple cellular compartments within each cell by multiplex fluorescent staining, followed by automated microscopy and image analysis. In this chapter, we show how to utilize data derived from images of fluorescently labeled cells and organelles while simultaneously addressing common challenges of this data type. We discuss different modes of interpreting raw cellular features and describe statistical methods for using said features to quantitatively evaluate overall assay quality and reproducibility. Data standardization is described as a two-tiered task, and the more recent EMD metric is implemented as a quantitative measure of phenotypic change. We illustrate each technique using data from an osteosarcoma (U-2 OS) high-content screening assay and describe all tools required to reproduce this work.
    Keywords:  Earth mover’s distance; High-content screening; Phenotypic profiling; Two-factor ANOVA
    DOI:  https://doi.org/10.1007/978-1-0716-4985-5_7
  6. medRxiv. 2025 Dec 22. pii: 2025.12.19.25342661. [Epub ahead of print]
      PTEN hamartoma tumor syndrome (PHTS) is a cancer predisposition disorder caused by germline PTEN variants, yet its full clinical spectrum remains poorly defined due to reliance on highly selected cohorts. Accordingly, PHTS is underrecognized and its prevalence underestimated. Leveraging genomic and electronic health record data from 414,830 participants in the All of Us (AoU) Research Program, we identified 55 individuals with pathogenic or likely pathogenic PTEN variants, the majority of whom lacked a prior PHTS diagnosis, underscoring underrecognition in the general population. PHTS affects ∼1/7500 individuals in this US cohort, which is about 26-folds higher than historical estimates for PTEN -related disorder. Compared with carriers of other cancer-related gene variants and noncarriers, PTEN variant carriers exhibited the highest cancer prevalence and significantly younger ages at first cancer diagnosis. Phenotype enrichment revealed expected overgrowth-related features as well as previously unreported associations, including adenotonsillar hypertrophy, sleep apnea, acanthosis nigricans, and extreme obesity, suggesting broader systemic involvement than classically appreciated. Variant spectra were consistent across the population-based and clinically-ascertained PHTS cohorts. These findings demonstrate that PHTS is more prevalent, more heterogeneous, and more often undiagnosed than current clinical practice reflects, emphasizing the value of population-scale genomics for comprehensive characterization and earlier detection of PHTS.
    DOI:  https://doi.org/10.64898/2025.12.19.25342661
  7. Front Bioinform. 2025 ;5 1684227
      Single-cell RNA sequencing (scRNA-seq) has generated a rapidly expanding collection of public datasets that provide insight into development, disease, and therapy. However, researchers lack an end-to-end solution for seamlessly retrieving, preprocessing, integrating, and analyzing these data because existing tools address only isolated steps and require manual curation of accessions, metadata, and technical variability, known as batch effects. In this study, we developed Celline, a Python package that executes an entire workflow using a single-line commands per step. Celline automatically gathers raw single-cell RNA-seq data from multiple public repositories and extracts metadata using large language models. It then wraps established tools, including Scrublet for doublet removal, Seurat and Scanpy for quality control and cell-type annotation, Harmony and scVI for batch correction, and Slingshot for trajectory inference, into one-line commands, enabling seamless integrative analyses. To validate Celline-acquired data quality and the integrated framework's practical utility, we applied it to 2 mouse brain cortex datasets from embryonic days 14.5 and 18. Technical validation demonstrated that Celline successfully retrieved data, standardized metadata, and enabled standard analyses that removed low-quality cells, annotated 11 major cell types, improved integration quality (scIB score +0.22), and completed trajectory analysis. Thus, Celline transforms scattered public scRNA-seq resources into unified, analysis-ready datasets with minimal effort. Its modular design allows pipeline extension, encourages community-driven advances, and accelerates the discovery of single-cell data.
    Keywords:  data management; integration; pipeline; public databases; python; single-cell RNA-seq
    DOI:  https://doi.org/10.3389/fbinf.2025.1684227
  8. Nat Rev Mol Cell Biol. 2026 Jan 02.
    Quantum for Healthcare Life Sciences Consortium
      The generation of highly accurate models of behaviours of individual cells and cell populations through integration of high-resolution assays with advanced computational tools would transform precision medicine. Recent breakthroughs in single-cell and spatial transcriptomics and multi-omics technologies, coupled with artificial intelligence, are driving rapid progress in model development. Complementing the advances in artificial intelligence, quantum computing is maturing as a novel compute paradigm that may offer potential solutions to overcome the computational bottlenecks inherent to capturing cellular dynamics. In this Roadmap article, we discuss the advancements and challenges in spatiotemporal single-cell analysis, explore the possibility of quantum computing to address the challenges and present a case study on how quantum computing may be integrated into cell-based therapeutics. The specific confluence of quantum and classical computing with high-resolution assays may offer a crucial path towards the generation of transformative models of cellular behaviours and perturbation responses.
    DOI:  https://doi.org/10.1038/s41580-025-00918-0
  9. J Chemother. 2026 Jan 02. 1-8
      Alpelisib, a selective phosphatidylinositol-3-kinase alpha (PI3Kα) inhibitor, improves outcomes in hormone receptor-positive (HR+), HER2-negative, PIK3CA-mutated advanced breast cancer, but rare serious toxicities such as pneumonitis may occur. We report a 79-year-old non-smoking woman with ER-positive/HER2-negative breast cancer who initially underwent breast-conserving surgery and adjuvant anastrozole in December 2023. Following local recurrence in October 2024, she received mastectomy and ribociclib-fulvestrant. Disease progression with nodal and osseous metastases was detected in April 2025. Liquid biopsy revealed a PIK3CA H1047R mutation, and alpelisib 150 mg daily plus fulvestrant was initiated in May 2025. After two months, she developed acute dyspnea and hypoxemia without fever. Imaging showed bilateral peripheral ground-glass opacities outside prior radiation fields, and infectious work-up was negative. Bronchoalveolar lavage supported drug-induced pneumonitis. Alpelisib was discontinued, and high-dose corticosteroids led to complete clinical and radiological resolution. This case highlights early-onset alpelisib-induced pneumonitis at a reduced dose and underscores the importance of early recognition and prompt management.
    Keywords:  Breast cancer; alpelisib; interstitial lung disease; oncotargeted therapies; pneumonitis; targeted therapies
    DOI:  https://doi.org/10.1080/1120009X.2025.2608457
  10. Cancer Cell. 2025 Dec 31. pii: S1535-6108(25)00543-4. [Epub ahead of print]
      Spatial omics transforms our understanding of cancer by revealing how tumor cells and the microenvironment are organized, interact, and evolve within tissues. Here, we synthesize advances in spatial technologies that map tumor ecosystems with unprecedented fidelity. We highlighted analytical breakthroughs-including multimodal integration and emerging spatial foundation models-that resolve functional niches and spatial communities, converting spatial patterns into mechanistic insights. We summarize how spatially organized features, from immune hubs to microbiota and neural interfaces, shape tumor evolution and clinical outcomes. We then outline how spatial approaches illuminate precancer biology, metastatic adaptation, and therapy response. Bridging discovery and translation, we provide a practical roadmap for incorporating spatial readouts into clinically oriented study design. We conclude by discussing persistent challenges in standardization and scalability and how high-plex spatial discoveries may be distilled into scalable, AI-enabled, clinically deployable assays, positioning spatial omics as a cornerstone of next-generation predictive and precision oncology.
    Keywords:  AI; ML; TME; artificial intelligence; cell-cell interaction; cellular neighborhood; computational pathology; machine learning; molecular imaging; multi-omics; multimodal data integration; proteomics; spatial biomarkers; spatial heterogeneity; spatial niche; spatial omics; transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.009
  11. J Exp Med. 2026 Mar 02. pii: e20241136. [Epub ahead of print]223(3):
      Modeling complex (patho)physiological processes by sequential targeted mutagenesis in mice is limited by the lack of precision of cellular targeting and complex breeding strategies. We present a new Cre/DreERT2 dual-recombinase germinal center B cell (GCBC)-specific strain, with co-expression of the recombinases from a single allele. This enables highly efficient Cre-mediated FOXO1 knockout in GCBCs in vivo, followed by time-controlled, efficient Dre-mediated FOXO1 re-expression in the same cells, leading to functional rescue of GC compartmentalization and class switch recombination. The present approach can be easily adapted to other cellular contexts.
    DOI:  https://doi.org/10.1084/jem.20241136
  12. Cancer Discov. 2025 Dec 31.
      Somatic mosaicism is pervasively observed in human aging, with clonal expansions of cells harboring mutations in recurrently mutated driver genes. Bulk sequencing of tissues captures mutation frequencies, but cannot reconstruct clonal architectures nor delineate how driver mutations impact cellular phenotypes. We developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, joint capture of genotyping of mutation hotspots and mRNA markers. We applied scG2P to aged esophagus samples from six individuals and observed large numbers of clones with a single driver event, accompanied by rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, while TP53 mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0853
  13. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2503783123
      Diabetes and insulin resistance (IR) remain major global health challenges, underscoring the need for novel therapeutic strategies. Here, we identify an autophagy-independent role of circulating autophagy-related gene 7 (ATG7) in metabolic regulation. Circulating ATG7 enhances insulin sensitivity and glucose homeostasis by directly interacting with IRS1 and modulating insulin signaling (IS) through liver-muscle crosstalk. Mechanistically, ATG7 binds to IRS1, promoting its activation and the propagation of downstream IS. Notably, we identify an ATG7-derived peptide (Aap2) that recapitulates ATG7's insulin-sensitizing effects and improves glycemic control in both Type 1 and Type 2 diabetic mouse models. These findings establish ATG7 as a key regulator of IS and suggest that targeting ATG7 may represent a promising therapeutic approach for IR and diabetes.
    Keywords:  ATG7; IRS1; exosomes; glucose homeostasis; insulin resistance
    DOI:  https://doi.org/10.1073/pnas.2503783123