bims-pideca 2025-08-31 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2025–08–31
eighteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

A computational workflow for assessing drug effects on temporal signaling dynamics reveals robustness in stimulus-specific NFκB signaling.
Tamoxifen induces PI3K activation in uterine cancer.
The promise and peril of comparing fluorescence lifetime in biology revealed by simulations.
Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics.
Single-cell proteomics using mass spectrometry.
Exploring Prenatal Signs of Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, and Skeletal Anomalies (CLOVES) Syndrome: A Case Report and Literature Review.
Quantitative profiling of human brain organoid cell diversity across four protocols and multiple cell lines.
Evolution and co-occurrence of PI3K pathway gene mutations in endometrial carcinoma molecular subtypes at the single-cell level.
Cells prioritize the regulation of cell mass density.
LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation.
DeepMVP: deep learning models trained on high-quality data accurately predict PTM sites and variant-induced alterations.
Recurrent Cellulitis in the Intergluteal Area in a Pediatric Patient with Klippel-Trenaunay Syndrome.
Identifying Protein-Protein Interaction or Protein Phosphorylation by Proximity Ligation Assay (PLA) in Endothelial Cells.
Diverse oncogenes use common mechanisms to drive growth of major forms of human cancer.
Molecular targeted treatment in infants with central conducting lymphatic anomalies.
Matrix-induced nuclear remodeling and mechano-therapeutics.
Tissue-specific consequences of tag fusions on protein expression in transgenic mice.
Ultrack: pushing the limits of cell tracking across biological scales.

PLoS Comput Biol. 2025 Aug;21(8): e1013344

A computational workflow for assessing drug effects on temporal signaling dynamics reveals robustness in stimulus-specific NFκB signaling.

Emily R Bozich, Xiaolu Guo, Jennifer L Wilson, Alexander Hoffmann.

Single-cell studies of signal transduction have revealed complex temporal dynamics that determine downstream biological function. For example, the stimulus-specific dynamics of the transcription factor NFκB specify stimulus-specific gene expression programs, and loss of specificity leads to disease. Thus, it is intriguing to consider drugs that may restore signaling specificity in disease contexts, or reduce activity but maintain signaling specificity to avoid unwanted side effects. However, while steady-state dose-response relationships have been the focus of pharmacological studies, there are no established methods for quantifying drug impact on stimulus-response signaling dynamics. Here we evaluated how drug treatments affect the stimulus-specificity of NFκB activation dynamics and its ability to accurately code ligand identity and dose. Specifically, we simulated the dynamic NFκB trajectories in response to 15 stimuli representing various immune threats under treatment of 10 representative drugs across 20 dosage levels. To quantify the effects on coding capacity, we introduced a Stimulus Response Specificity (SRS) score and a stimulus confusion score. We constructed stimulus confusion maps by employing epsilon network clustering in the trajectory space and in various dimensionally reduced spaces: canonical polyadic decomposition (CPD), functional principal component analysis (fPCA), and NFκB signaling codons (i.e., established, informative dynamic features). Our results indicated that the SRS score and the stimulus confusion map based on signaling codons are best-suited to quantify stimulus-specific NFκB dynamics confusion under pharmacological perturbations. Using these tools we found that temporal coding capacity of the NFκB signaling network is generally robust to a variety of pharmacological perturbations, thereby enabling the targeting of stimulus-specific dynamics without causing broad side-effects.

DOI: https://doi.org/10.1371/journal.pcbi.1013344
Nat Genet. 2025 Aug 22.

Tamoxifen induces PI3K activation in uterine cancer.

Kirsten Kübler, Agostina Nardone, Shankara Anand, Daniel Gurevich, Jianjiong Gao, Marjolein Droog, Francisco Hermida-Prado, Tara Akhshi, Ariel Feiglin, Avery S Feit, Gabriella Cohen Feit, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, Sebastian Gregoricchio, Mirthe Lanfermeijer, Sten Cornelissen, William J Gibson, Cloud P Paweletz, Eliezer M Van Allen, Flora E van Leeuwen, Petra M Nederlof, Quang-Dé Nguyen, Marian J E Mourits, Milan Radovich, Ignaty Leshchiner, Chip Stewart, Ursula A Matulonis, Wilbert Zwart, Yosef E Maruvka, Gad Getz, Rinath Jeselsohn.

Mutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors. In vivo, tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue, potentially eliminating the selective benefit of PI3K-activating mutations in tamoxifen-associated uterine cancer. Together, we present a unique pathway of therapy-associated carcinogenesis in which tamoxifen-induced activation of the PI3K pathway acts as a non-genetic driver event, contributing to the multistep model of uterine carcinogenesis. While this PI3K mechanism is specific to tamoxifen-associated uterine cancer, the concept of treatment-induced signaling events may have broader applicability to other routes of tumorigenesis.

DOI: https://doi.org/10.1038/s41588-025-02308-w
Elife. 2025 Aug 20. pii: RP101559. [Epub ahead of print]13

The promise and peril of comparing fluorescence lifetime in biology revealed by simulations.

Pingchuan Ma, Peter Chen, Scott Sternson, Yao Chen.

  Signaling dynamics are crucial in biological systems, and biosensor-based real-time imaging has revolutionized their analysis. Fluorescence lifetime imaging microscopy (FLIM) excels over the widely used fluorescence intensity imaging by allowing the measurement of absolute signal levels independent of sensor concentration. This capability enables the comparison of signaling dynamics across different animals, body regions, and timeframes. However, FLIM's advantage can be compromised by factors like autofluorescence in biological experiments. To address this, we introduce FLiSimBA, a flexible computational framework for realistic Fluorescence Lifetime Simulation for Biological Applications. Through simulations, we analyze the signal-to-noise ratios of fluorescence lifetime data, determining measurement uncertainty and providing necessary error bars for lifetime measurements. Furthermore, we challenge the belief that fluorescence lifetime is unaffected by sensor expression and establish quantitative limits to this insensitivity in biological applications. Additionally, we propose innovations, notably multiplexed dynamic imaging that combines fluorescence intensity and lifetime measurements. This innovation can transform the number of signals that can be simultaneously monitored, thereby enabling a systems approach in studying signaling dynamics. Thus, by incorporating different factors into our simulation framework, we uncover surprises, identify limitations, and propose advancements for fluorescence lifetime imaging in biology. This quantitative framework supports rigorous experimental design, facilitates accurate data interpretation, and paves the way for technological advancements in fluorescence lifetime imaging.

Keywords:  FLiSimBA; biosensor; cell biology; fluorescence lifetime; multiplexed dynamic imaging; neuroscience; none; sensor expression; simulation

DOI:  https://doi.org/10.7554/eLife.101559
Science. 2025 Aug 21. eadr8785

Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics.

Benjamin Furtwängler, Nil Üresin, Sabrina Richter, Mikkel Bruhn Schuster, Despoina Barmpouri, Henrietta Holze, Anne Wenzel, Kirsten Grønbæk, Kim Theilgaard-Mönch, Fabian J Theis, Erwin M Schoof, Bo T Porse.

Single-cell transcriptomics (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of mRNA measurements comes at the risk of missing important biological information. Here we leveraged recent technological advances in single-cell proteomics by Mass Spectrometry (scp-MS) to generate an scp-MS dataset of an in vivo differentiation hierarchy encompassing over 2500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identified proteins that are important for stem cell function, which were not indicated by their mRNA transcripts. Further, we showed that modeling translation dynamics can infer cell progression during differentiation and explain substantially more protein variation from mRNA than linear correlation. Our work offers a framework for single-cell multi-omics studies across biological systems.

DOI: https://doi.org/10.1126/science.adr8785
Cell Genom. 2025 Aug 13. pii: S2666-979X(25)00229-0. [Epub ahead of print] 100973

Single-cell proteomics using mass spectrometry.

Amanda Momenzadeh, Jesse G Meyer.

Over the past 2 to 3 years, mass-spectrometry-based single-cell proteomics (SCP) has experienced transformative improvements in microfluidic and robotic sample preparation, innovative MS1- and MS2-based multiplexing strategies, and specialized hardware (e.g., timsTOF Ultra 2, Astral), which have dramatically boosted sensitivity, throughput, and proteome coverage from picogram-level protein inputs. Concurrently, tailored computational workflows that encompass normalization, imputation, and no-code platforms have addressed pervasive missing data challenges and standardized analyses, collectively enabling high-throughput, reproducible profiling of cellular heterogeneity. This minireview summarizes the latest progress in SCP technology and software solutions, highlighting how the closer integration of analytical, computational, and experimental strategies will facilitate a deeper and broader coverage of single-cell proteomes.

DOI: https://doi.org/10.1016/j.xgen.2025.100973
Cureus. 2025 Jul;17(7): e88455

Exploring Prenatal Signs of Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, and Skeletal Anomalies (CLOVES) Syndrome: A Case Report and Literature Review.

Emily Henuzet, Laurence Boon, Dana Dumitriu, Leentje Peetermans, Patricia Steenhaut.

  We report a rare case of partial prenatal diagnosis of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies (CLOVES) syndrome in a fetus presenting extensive dorsal lymphatic malformation, bilateral polydactyly and syndactyly, hypertrophy on the left foot, and suspected cryptorchidism. Amniocentesis with comparative genomic hybridization (CGH) and trio-exome sequencing did not reveal any pathogenic variant. Postnatal clinical examination and imaging confirmed the malformations, including a multilocular macrocystic lymphatic malformation with retroperitoneal extension. Sirolimus therapy was initiated, resulting in a modest reduction in the volume of the dorsal mass within the first two months of treatment. This report underscores key prenatal features that may raise suspicion for CLOVES syndrome, helping clinicians to differentiate it from other overgrowth disorders such as Proteus syndrome and conditions within phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), supporting improved diagnosis and counseling during pregnancy.

Keywords:  antenatal diagnosis; cloves syndrome; pik3ca mutation; pros; segmental overgrowth; vascular malformations

DOI:  https://doi.org/10.7759/cureus.88455
Cell Rep. 2025 Aug 25. pii: S2211-1247(25)00939-8. [Epub ahead of print]44(9): 116168

Quantitative profiling of human brain organoid cell diversity across four protocols and multiple cell lines.

Julia Naas, Meritxell Balmaña, Laurenz Holcik, Maria Novatchkova, Lina Dobnikar, Thomas Krausgruber, Sabrina Ladstätter, Christoph Bock, Arndt von Haeseler, Christopher Esk, Jürgen A Knoblich.

  Human brain organoids are powerful in vitro models for brain development and disease. However, protocol and pluripotent cell line choices influence organoid variability and cell-type representation, complicating their use in biomedical research. Here, we systematically analyze the cellular and transcriptional landscape of brain organoids across multiple cell lines using four protocols aimed at recapitulating dorsal and ventral forebrain, midbrain, and striatum. We introduce the NEST-Score to evaluate cell-line- and protocol-driven differentiation propensities and comparisons to in vivo references. Thereby, we establish a set of protocols that together recreate the majority of cell types in the developing brain and provide a reference of cell-type recapitulation across cell lines and protocols. Additionally, we identify early gene expression signatures predicting protocol-driven organoid generation. We provide easy access to our data through a web explorer, creating a reference for brain organoid research and allowing straightforward protocol and cell-line performance validation.

Keywords:  CP: Stem cell research; brain development; brain organoid; computational tool; scRNA-seq; time-resolved RNA-seq

DOI:  https://doi.org/10.1016/j.celrep.2025.116168
Clin Cancer Res. 2025 Aug 20.

Evolution and co-occurrence of PI3K pathway gene mutations in endometrial carcinoma molecular subtypes at the single-cell level.

Arnaud Da Cruz Paula, Yingjie Zhu, David N Brown, Shirin Issa Bhaloo, Fresia Pareja, Timothy J Hoang, Hunter Green, Thais Basili, Higinio Dopeso, Pier Selenica, Edaise M da Silva, Nadeem Riaz, Sarat Chandarlapaty, Nadeem R Abu-Rustum, Jorge S Reis-Filho, Britta Weigelt.

PURPOSE: The PI3K pathway is altered in >85% of endometrioid endometrial carcinomas (EECs), with multiple mutations commonly co-occurring. Yet, the therapeutic effects of single-agent PI3K pathway inhibitors have been limited. We used single-cell sequencing to determine whether co-occurring PTEN, PIK3CA, and/or PIK3R1 somatic mutations in EECs stratified by molecular subtype originated through convergent or linear evolution.
METHODS: Banked frozen EECs with co-occurring PI3K pathway mutations of no specific molecular profile (NSMP; n=5), mismatch repair-deficient (MMRd;n=3), and POLE (n=3) subtype were selected for single-nucleus DNA sequencing targeting hotspot variants of 64 cancer-related genes and the PTEN, PIK3R1 and PIK3CA coding sequences. EEC cell lines and non-malignant samples were used to define error rates and filter false-positive calls.
RESULTS: Single-nucleus analyses (n=50,009 cells) revealed that in NSMP EECs, the co-occurring PIK3CA, PIK3R1, and/or PTEN mutations affected nearly all cells through linear evolution. MMRd EECs displayed higher levels of genetic heterogeneity, harboring PI3K pathway gene mutations in subsets of cells ranging from 3.9%-96%. POLE EECs had the highest level of clonal diversity and harbored multiple minor subclonal structures in all cases, through convergent evolution. We found a clear distinction between nearly clonal PI3K pathway gene alterations (>95%) and multiple minor, mutually-exclusive subclones only affecting 1.4%-27% of the tumor cells sequenced.
CONCLUSIONS: Our exploratory, hypothesis-generating analysis suggest that PI3K pathway alterations evolve distinctly in MMRd/POLE compared to NSMP EECs, which may have therapeutic consequences. Further studies on the signaling output and PI3K pathway inhibitor response in EECs with subclonal PI3K pathway alterations are warranted.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1237
Sci Adv. 2025 Aug 29. 11(35): eadv9759

Cells prioritize the regulation of cell mass density.

Jinyu Fu, Qin Ni, Yufei Wu, Anoushka Gupta, Zhuoxu Ge, Hongru Yang, Yasin Afrida, Ishan Barman, Sean X Sun.

A cell's global physical state is characterized by its volume and dry mass. The ratio of cell mass to volume defines the cell mass density (CMD), which is also a measure of macromolecular crowding and concentrations of all proteins. Using the fluorescence eXclusion method (FXm) and quantitative phase microscopy (QPM), we investigate CMD dynamics following sudden changes in media osmolarity. We find that while cell volume and mass exhibit complex behavior after osmotic shock, CMD follows a straightforward monotonic recovery over 48 hours. This recovery is cell cycle independent and depends on coordinated adjustment of protein synthesis and volume growth rates. Unexpectedly, the protein synthesis rate decreases when CMD increases. We observe that nucleoplasm-cytoplasm transport is CMD dependent, which contributes to negative regulatory feedback on CMD. The Na+/H+ exchanger helps regulate CMD by affecting both protein synthesis and volume change. Together, we reveal that cells have a robust control system that actively regulates CMD during environmental change.

DOI: https://doi.org/10.1126/sciadv.adv9759
Nat Commun. 2025 Aug 21. 16(1): 7812

LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation.

Dhanusha A Nalawansha, Georgios Mazis, Gitte Husemoen, Kate S Ashton, Weixian Deng, Ryan P Wurz, Anh T Tran, Brian A Lanman, Jiansong Xie, Robert G Guenette, Shiqian Li, Christopher E Smith, Suresh Archunan, Manoj K Agnihotram, Arghya Sadhukhan, Rajiv Kapoor, Chris Wilde, Sajjan Koirala, Felipe De Sousa E Melo, Patrick Ryan Potts.

Proximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LYsosome Membrane TArgeting Chimeras (LYMTACs) as a small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. We extend this concept by showing that oncogenic KRASG12D signaling can be potently inhibited by LYMTACs. Mechanistically, LYMTACs display multi-pharmacology and exert their activity through both target relocalization into the lysosome and degradation. We further generalize LYMTACs across various LMPs and thus offer a platform to access challenging membrane proteins through targeted protein relocalization and degradation.

DOI: https://doi.org/10.1038/s41467-025-63128-4
Nat Methods. 2025 Aug 26.

DeepMVP: deep learning models trained on high-quality data accurately predict PTM sites and variant-induced alterations.

Bo Wen, Chenwei Wang, Kai Li, Ping Han, Matthew V Holt, Sara R Savage, Jonathan T Lei, Yongchao Dou, Zhiao Shi, Yi Li, Bing Zhang.

Post-translational modifications (PTMs) are critical regulators of protein function, and their disruption is a key mechanism by which missense variants contribute to disease. Accurate PTM site prediction using deep learning can help identify PTM-altering variants, but progress has been limited by the lack of large, high-quality training datasets. Here, we introduce PTMAtlas, a curated compendium of 397,524 PTM sites generated through systematic reprocessing of 241 public mass-spectrometry datasets, and DeepMVP, a deep learning framework trained on PTMAtlas to predict PTM sites for phosphorylation, acetylation, methylation, sumoylation, ubiquitination and N-glycosylation. DeepMVP substantially outperforms existing tools across all six PTM types. Its application to predicting PTM-altering missense variants shows strong concordance with experimental results, validated using literature-curated variants and cancer proteogenomic datasets. Together, PTMAtlas and DeepMVP provide a robust platform for PTM research and a scalable framework for assessing the functional consequences of coding variants through the lens of PTMs.

DOI: https://doi.org/10.1038/s41592-025-02797-x
R I Med J (2013). 2025 Sep 02. 108(9): 19-21

Recurrent Cellulitis in the Intergluteal Area in a Pediatric Patient with Klippel-Trenaunay Syndrome.

Francy D Vera-Amaya, Jorge I Gomez-Restrepo, Oscar D Fontecha, Ashley B Wentworth, Elisha Singer, Thais Pincelli, Miguel A Aristizabal-Torres.

Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder associated with somatic mutations in the PIK3CA gene, characterized classically by a triad of capillary malformations, venous malformations, and soft tissue and bone hypertrophy. While KTS commonly involves a single lower extremity, we present an atypical pediatric case featuring extensive venolymphatic malformation of the intergluteal region. This uncommon anatomical localization predisposed the patient to recurrent episodes of cellulitis, significantly complicating clinical management. This case underscores the importance of recognizing atypical presentations of KTS and the heightened susceptibility to recurrent infections, such as cellulitis, which may significantly impact morbidity and patient care.

Keywords: Klippel-Trenaunay-Weber syndrome; cellulitis; venous malformation
Methods Mol Biol. 2025 ;2956 143-155

Identifying Protein-Protein Interaction or Protein Phosphorylation by Proximity Ligation Assay (PLA) in Endothelial Cells.

Eleni Mourkogianni, Marina Koutsioumpa, Evangelia Papadimitriou.

  Proximity ligation assay (PLA) is a method that allows the identification of epitopes located in the immediate vicinity (distance <40 nm) of each other, in cultured cells or tissue samples. It is used for the in situ detection of protein-protein interactions or to detect and quantify protein modifications with high sensitivity. The locations of proximate epitopes appear as dots detected by confocal microscopy. In this chapter, we describe an optimized protocol in endothelial cells that can be used to identify protein-protein interactions (e.g., direct interaction of ανβ3 integrin with neuropilin-1) or protein phosphorylation (e.g., phosphorylation of ribosomal protein S6 kinase B1 (S6K1)), which is a biomarker for mTORC1 activation. Representative confocal microscope photos are presented, and methods to quantify the results are discussed.

Keywords:  Posttranslational protein modification; Protein phosphorylation; Protein–protein interaction; Proximity ligation assay (PLA)

DOI:  https://doi.org/10.1007/978-1-0716-4706-6_13
Sci Adv. 2025 Aug 22. 11(34): eadt1798

Diverse oncogenes use common mechanisms to drive growth of major forms of human cancer.

Otto Kauko, Mikko Turunen, Päivi Pihlajamaa, Antti Häkkinen, Rayner M L Queiroz, Mirva Pääkkönen, Sami Ventelä, Massimiliano Gaetani, Susanna L Lundström, Antonio Murgia, Biswajyoti Sahu, Johannes Routila, Gong-Hong Wei, Heikki Irjala, Julian L Griffin, Kathryn S Lilley, Teemu Kivioja, Sampsa Hautaniemi, Jussi Taipale.

Mutations in numerous genes contribute to human cancer, with different oncogenic lesions prevalent in different cancer types. However, the malignant phenotype is simple, characterized by unrestricted cell growth, invasion, and often metastasis. One possible hypothesis explaining this dichotomy is that cancer genes regulate common targets, which then function as master regulators of essential cancer phenotypes. To identify mechanisms that drive the most fundamental feature shared by all tumors-unrestricted cell proliferation-we used a multiomic approach, which identified translation and ribosome biogenesis as common targets of major oncogenic pathways across cancer types. Proteomic analysis of tumors and functional studies of cell cultures established nucleolar and coiled-body phosphoprotein 1 as a key node, whose convergent regulation, both transcriptionally and posttranslationally, is critical for tumor cell proliferation. Our results indicate that lineage-specific oncogenic pathways regulate the same set of targets for growth control, revealing key downstream nodes that could be targeted for therapy or chemoprevention.

DOI: https://doi.org/10.1126/sciadv.adt1798
Eur J Pediatr. 2025 Aug 21. 184(9): 567

Molecular targeted treatment in infants with central conducting lymphatic anomalies.

Vera C van den Brink, Lotte E R Kleimeier, Erika K S M Leenders, Willemijn M Klein, Willem P de Boode, Joris Fuijkschot, Sabine L A G Vrancken.

  Central conducting lymphatic anomaly (CCLA) is a rare and potentially life-threatening vascular malformation characterized by impaired central lymphatic flow. Hydrops fetalis and congenital hydro-/chylothorax are common neonatal presentations; however, diagnosing CCLA poses challenges and requires advanced imaging. Management typically includes supportive therapies with limited effect, such as medium-chain triglyceride (MCT) diet, octreotide or propranolol, and thoracic drainage. Upcoming treatment options with mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MEK) inhibitors have shown promising results in vascular anomalies driven by dysregulated PI3K/AKT/mTOR and RAS/RAF/MAPK signalling pathways. However, data on neonatal use remain scarce. This series describes infants (gestational age 29 + 3-40 + 4 weeks) with neonatal-onset CCLA treated with mTOR and/or MEK inhibitors (age IQR: 27-57 days), detailing clinical presentations, imaging, genetic findings, and outcomes. Genetic testing included germline and somatic variant analysis. Most patients underwent dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) for diagnosis and to guide management. Pathogenic germline variants were identified in four patients; three had no genetic diagnosis. DCMRL revealed heterogeneous phenotypes; follow-up imaging showed improved lymphatic flow. Substantial clinical improvement occurred following mTOR and/or MEK inhibitor treatment (sirolimus and/or trametinib). In most cases, therapy was tapered within weeks; no relapses occurred (mean follow-up 10.3 months). No deaths or other severe adverse events occurred during inhibitor treatment.
CONCLUSION: This series describes infants with CCLA, treated with mTOR and/or MEK inhibitors early after birth, with rapid improvement possibly reflecting treatment response leading to functional recovery during a critical developmental phase of the lymphatic system.
WHAT IS KNOWN: • Central conducting lymphatic anomalies are rare conditions associated with high morbidity and mortality, especially in neonates. • Molecular targeted therapies such as MEK inhibitors and mTOR inhibitors show promise in vascular anomalies driven by upregulated PI3K/AKT/mTOR and RAS/RAF/MAPK signalling pathways.
WHAT IS NEW: • This series offers a detailed description of the early disease course, clinical variation, and management in infants with congenital chylothorax/hydrops fetalis due to CCLA, contributing to a better understanding of this rare condition in the neonatal period. • Early treatment with low-dose mTOR and/or MEK inhibitors seems effective in infants with CCLA, potentially reducing morbidity and mortality.

Keywords:  Central conducting lymphatic anomaly; Complex lymphatic anomaly; Congenital chylothorax; Hydrops fetalis; Sirolimus; Trametinib

DOI:  https://doi.org/10.1007/s00431-025-06376-2
Cell Rep. 2025 Aug 22. pii: S2211-1247(25)00947-7. [Epub ahead of print]44(9): 116176

Matrix-induced nuclear remodeling and mechano-therapeutics.

Jung-Hwan Lee, Yeo Gyun Yun, Hae-Won Kim.

  The extracellular matrix (ECM) provides structural support and mechanical cues that profoundly influence cellular behavior via nuclear mechanotransduction. This review discusses how ECM biophysical properties, including stiffness, topology, and spatial confinement, regulate nuclear mechanics and chromatin organization to determine cell fate across diverse pathophysiological contexts. We describe how mechanical signals propagate from the plasma membrane through cytoskeletal networks to modulate nuclear envelope tension, chromatin accessibility, and epigenetic landscapes. These matrix-driven nuclear changes orchestrate cellular responses in cancer progression, inflammation, fibrosis, stem cell differentiation, and age-related tissue dysfunction. Building on this mechanistic insight, we highlight emerging therapeutic strategies targeting the matrix-nucleus axis, such as tuning matrix properties to modulate chromatin accessibility, mechano-priming cells to enhance therapeutic outcomes, and targeting mechanosensitive molecules in the cytoskeletal-nuclear interface. Collectively, these approaches represent a promising paradigm leveraging mechanically induced epigenetic regulation and nuclear mechanobiology for disease treatment and tissue regeneration.

Keywords:  CP: Cell biology

DOI:  https://doi.org/10.1016/j.celrep.2025.116176
PLoS Genet. 2025 Aug 25. 21(8): e1011830

Tissue-specific consequences of tag fusions on protein expression in transgenic mice.

Gillian C A Taylor, Lewis Macdonald, Natalia A Szulc, Evelina Gudauskaite, Brianda Hernandez Moran, Jennifer M Brisbane, Molly Donald, Ella Taylor, Dejin Zheng, Bin Gu, Pleasantine Mill, Patricia L Yeyati, Wojciech Pokrzywa, Claudia Ribeiro de Almeida, Andrew J Wood.

Genetic fusion of protein tags is widely used to study protein functions in vivo. It is well known that tag fusion can cause unwanted changes in protein stability, but whether this is an inherent property of the tagged protein, or can be influenced by the cell and tissue environment, is unclear. Using a series of genome edited mouse models, we show that tag-dependent changes in protein expression can vary across different primary cell and tissue contexts. In one case (Ncaph2), a C-terminal auxin-inducible degron fusion strongly increased protein stability in some tissues but decreased it in others. Destabilisation resulted from tissue-specific 'leakage' of the auxin-inducible degron, which depended on TIR1 expression, and occurred selectively in the small intestine where basal concentrations of auxin/ indole-3-acetic acid can reach levels that are sufficient to trigger protein degradation in cultured cells. Stabilisation occurred in post-mitotic cells via an endogenous degradation signal situated at the NCAPH2 C-terminus, which normally undergoes activation upon cell cycle exit, but is inactivated by C-terminal tag fusion. Our results highlight the underappreciated importance of cell and tissue environment in determining the consequences of tag fusions on protein expression, which may be particularly important in animal models that contain diverse cell types.

DOI: https://doi.org/10.1371/journal.pgen.1011830
Nat Methods. 2025 Aug 25.

Ultrack: pushing the limits of cell tracking across biological scales.

Jordão Bragantini, Ilan Theodoro, Xiang Zhao, Teun A P M Huijben, Eduardo Hirata-Miyasaki, Shruthi VijayKumar, Akilandeswari Balasubramanian, Tiger Lao, Richa Agrawal, Sheng Xiao, Jan Lammerding, Shalin Mehta, Alexandre X Falcão, Adrian Jacobo, Merlin Lange, Loïc A Royer.

Tracking live cells across two-dimensional, three-dimensional (3D) and multichannel time-lapse recordings is crucial for understanding tissue-scale biological processes. Despite advancements in imaging technology, accurately tracking cells remains challenging, particularly in complex and crowded tissues where cell segmentation is often ambiguous. We present Ultrack, a versatile and scalable cell tracking method that tackles this challenge by considering candidate segmentations derived from multiple algorithms and parameter sets. Ultrack leverages temporal consistency to select optimal segments, ensuring robust performance even under segmentation uncertainty. We validate our method on diverse datasets, including terabyte-scale developmental time-lapse recordings of zebrafish, fruit fly and nematode embryos, as well as multicolor and label-free cellular imaging. We demonstrate that Ultrack achieves superior or comparable performance in the cell tracking challenge, particularly when tracking densely packed 3D embryonic cells over extended periods. Moreover, we propose an approach to tracking validation via dual-channel sparse labeling that enables high-fidelity ground-truth generation, pushing the boundaries of long-term cell tracking assessment. Our method is freely available as a Python package with Fiji and Napari plugins and can be deployed in a high-performance computing environment, facilitating widespread adoption by the research community.

DOI: https://doi.org/10.1038/s41592-025-02778-0