bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–12–21
twenty-one papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Non-redundant roles of the phosphoinositide phosphatases PTEN and PIPP in PI3K/AKT signaling in breast cancer.
  2. Rescue of Angiopoietin-2 Inhibits Proliferation of Lymphatic Malformation Endothelial Cells.
  3. Dual PI3K/mTOR inhibition is required to combat resistance to CDK4/6 inhibitor and endocrine therapy in PIK3CA-mutant breast cancer.
  4. Cellular responses to FGF1 are modulated by palmitoylation of the docking protein FRS2α.
  5. FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth.
  6. CRISPR screens in human neural organoids and assembloids.
  7. Apelin signaling acts as a molecular switch between endothelial and hematopoietic stem cell fates.
  8. PhotoFiTT: a quantitative framework for assessing phototoxicity in live-cell microscopy experiments.
  9. Carta offers a computational approach to inference of differentiation maps from cell lineages.
  10. Host PI3K inhibition via anti-cancer drug alpelisib influences Influenza A non-infectious particles and deletion-containing viral genomes.
  11. SpaceBar enables single-cell-resolution clone tracing with imaging-based spatial transcriptomics.
  12. The power of five - inositol polyphosphate 5-phosphatase gene mutations at the intersection of development and disease.
  13. MultiCell: geometric learning in multicellular development.
  14. Evaluating transportability of in vitro cellular models to in vivo human phenotypes using gene perturbation data.
  15. Concurrent PIK3CA mutant promotes cachexia through inflammatory signaling in EGFR mutant lung cancer.
  16. The fate of pyruvate dictates cell growth by modulating cellular redox potential.
  17. Development of Long-Term Human Adipocyte Organoids Manifesting Aging in Response to Intermittent Hypoxia.
  18. Challenges and opportunities for oncology drug repurposing informed by synthetic lethality.
  19. Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.
  20. Multi-omics analysis reveals metabolic diversity underlying endothelial cell functions.
  21. The 'vulnerability code': Is cell identity the architect of its own decay?
  1. Commun Biol. 2025 Dec 17.
    Non-redundant roles of the phosphoinositide phosphatases PTEN and PIPP in PI3K/AKT signaling in breast cancer.
    Lisa M Ooms, Daniel T Ferguson, Samuel J Rodgers, Karmanpreet K Sukhija, Emily I Jones, Mariah P Csolle, Hon Yan Kelvin Yip, Roger J Daly, Tony Tiganis, Catriona A McLean, Antonella Papa, Christina A Mitchell.
      Phosphoinositide 3-kinase (PI3K) signaling is hyperactivated in ~70% of breast cancers via mutations in oncogenes including PIK3CA or inactivation/depletion of phosphoinositide (PI)-phosphatases. Generation of PI(3,4,5)P3 by PI3K activates many downstream effectors, including AKT, that induce cellular proliferation in breast cancer. In this context PI(3,4,5)P3 is tightly regulated by PI-phosphatases, including the tumor suppressor PTEN and inositol polyphosphate 5-phosphatases such as PIPP/INPP5J. PTEN and PIPP dephosphorylate PI(3,4,5)P3 to form different lipid products, thereby individually regulating AKT activation. PI3K/AKT signaling is complex and the functional interplay between these PI-phosphatases in suppressing this pathway in vivo is unknown. Here, we utilize experimental models of breast cancer, both dependent and independent of PIK3CA mutation. Pipp ablation in Pten+/- mice increases mammary AKT signaling and cell proliferation, associated with increased hyperplasia and ductal thickening, characteristics linked with mammary epithelial cell transformation. In breast cancer cell lines, combined PIPP/PTEN knockdown increases AKT signaling and cell proliferation, independent of mutant PIK3CA, above any single PI-phosphatase knockdown. Notably, combined PIPP/PTEN loss is observed in a subset of human breast cancers, associated with reduced survival. Collectively, these findings support a model whereby loss of PIPP constitutes a co-operative step towards breast cancer progression in the context of PTEN deficiency.
    DOI:  https://doi.org/10.1038/s42003-025-09364-2
  2. FASEB J. 2025 Dec 31. 39(24): e71308
    Rescue of Angiopoietin-2 Inhibits Proliferation of Lymphatic Malformation Endothelial Cells.
    Ravi W Sun, Haihong Zhang, Syed J Mehdi, Jordan K Bowen, Alexander K Burnett, Gresham T Richter, Charity L Washam, Stephanie D Byrum, June K Wu, Carrie J Shawber, Graham M Strub.
      Cystic lymphatic malformations (LMs) are congenital anomalies characterized by the formation of dilated lymphatic channels that can infiltrate adjacent structures and cause significant morbidity. Somatic activating single nucleotide variants in PIK3CA have been identified in the majority of these lesions, yet the precise mechanisms underlying the role of these variants in LM progression remain unclear. Here, we investigated the role of Angiopoietin-2 (Ang2) downregulation downstream of pathogenic PIK3CA variants in the pathogenesis of LMs and delineated a novel inhibitory mechanism for autocrine Ang2 in the lymphatic vasculature. Transcriptomic profiling of patient-derived LM endothelial cells (LMECs) with PIK3CA variants revealed Ang2 as one of the most significantly downregulated genes. Overexpression of ANG2 in LMECs and normal human dermal lymphatic endothelial cells significantly suppressed their proliferation and inhibited VEGFR3 expression. In contrast, non-cell autonomous derived or exogenous ANG2 significantly promoted LMEC viability and increased AKT activity. Treatment of LMECs with the PI3K inhibitor alpelisib, but not the mTOR inhibitor sirolimus (rapamycin), rescued autocrine ANG2 expression and significantly downregulated VEGFR3. Alpelisib or sirolimus in combination with ANG2 overexpression significantly reduced LMEC viability compared to ANG2 overexpression or drug treatment alone. Finally, ANG2 overexpression in LMECs suppressed the LM phenotype in a murine xenograft model. Together, our findings suggest that targeting autocrine Ang2 signaling may be a viable option for suppressing pathological lymphangiogenesis.
    Keywords:  alpelisib; angiopoietin‐2; lymphangiogenesis; lymphatic malformation; sirolimus
    DOI:  https://doi.org/10.1096/fj.202502078R
  3. Sci Transl Med. 2025 Dec 17. 17(829): eadp5088
    Dual PI3K/mTOR inhibition is required to combat resistance to CDK4/6 inhibitor and endocrine therapy in PIK3CA-mutant breast cancer.
    Carla L Alves, Leena Karimi, Mikkel G Terp, Mie K Jakobsen, Fiona H Zhou, Benedetta Policastro, Nikoline Nissen, Lene E Johansen, Tina Ravnsborg, Leila Eshraghi, Sana Tamboowala, Ole N Jensen, Elgene Lim, Henrik J Ditzel.
      Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) improves outcomes in advanced estrogen receptor-positive (ER+) breast cancer, but emergence of resistance to this combination underscores the pressing need for alternative therapeutic strategies. A promising approach involves adding an inhibitor of the PI3K/AKT/mTOR pathway to the standard combined CDK4/6i and ET, but selecting the most effective inhibitors and their optimal combinations has proven to be challenging. Here, we compared the efficacy of various triple combinations using single- or dual-point PI3K/AKT/mTOR pathway inhibitors in breast cancer cell lines, cell line xenografts, patient-derived xenografts, and organoids resistant to CDK4/6i and ET and exhibiting PIK3CA, PTEN, or AKT1 mutations. PIK3CA-mutant, PTEN-wild type, CDK4/6i-resistant, and ET-resistant models required the addition of the dual PI3K/mTOR inhibitor gedatolisib to effectively impede tumor growth by blocking the HIF-1α pathway through both mTORC1 inhibition and PI3K/AKT-mediated modulation of GSK3α/β activity. Conversely, PIK3CA-wild type, PTEN-null cells benefited from triple combinations incorporating either the AKT inhibitor capivasertib or the dual mTORC1/2 inhibitor sapanisertib to block tumor growth. In addition, gedatolisib reduced viability of PIK3CA- or AKT1-mutant and PTEN-wild type CDK4/6i-resistant patient-derived organoids compared with the α-specific PI3K inhibitor alpelisib. Our data support the higher efficacy of gedatolisib over alpelisib in ER+ breast tumors harboring alterations of the PI3K/AKT/mTOR pathway including PIK3CA or AKT1 mutations.
    DOI:  https://doi.org/10.1126/scitranslmed.adp5088
  4. bioRxiv. 2025 Dec 13. pii: 2025.12.11.693497. [Epub ahead of print]
    Cellular responses to FGF1 are modulated by palmitoylation of the docking protein FRS2α.
    Seong An, Yoshihisa Suzuki, Jyotidarsini Mohanty, Francisco Tome, Irit Lax, Joseph Schlessinger.
      An important mechanism by which receptor tyrosine kinases (RTKs) mediate cellular responses involves the formation of signaling complexes through direct interactions with membrane-associated docking proteins, followed by phosphorylation of multiple tyrosine residues. These docking proteins recruit and activate downstream signaling molecules and enzymes following ligand stimulation. The docking protein FRS2α has been established as a major signaling hub activated by fibroblast growth factors (FGFs), neurotrophic factors, and other extracellular cues. Here, we show that palmitoylation of FRS2α at two sites is essential for stabilizing its myristoylation-dependent association with the plasma membrane. FGF1-induced MAPK activation and other cellular responses are partially restored in cells expressing FRS2α mutants deficient in either one of the two palmitoylation sites. However full restoration of signal strength including MAPK response and other FGF1-induced cellular activities requires palmitoylation at both FRS2α sites. In addition to enhancing signaling robustness, anchoring of FRS2α to the plasma membrane creates a structural platform for assembling multi-protein complexes essential for cytoskeletal reorganization associated with membrane ruffling, macropinocytosis, and other FGF1-induced processes. Finally, we demonstrate that while PC12 cells lacking FRS2α or deficient in FRS2α palmitoylation can proliferate, FGF1-induced neuronal differentiation strictly depends on the palmitoylation of the docking protein.
    DOI:  https://doi.org/10.64898/2025.12.11.693497
  5. J Clin Invest. 2025 Dec 16. pii: e195031. [Epub ahead of print]
    FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth.
    Jianfang Gao, Jina Qing, Xianglong Li, Yuxuan Luo, Lingwen Huang, Hongxia Li, Huan Zhang, Jiao Zhang, Pei Xiao, Jinsong Li, Tingting Li, Shanping He.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a master controller of cell growth and its dysregulation is associated with cancer. KICSTOR, a complex comprising KPTN, ITFG2, C12orf66, and SZT2, functions as a critical negative regulator of amino acid-induced mTORC1 activation. However, the regulatory mechanisms governing KICSTOR remain largely unclear. In this study, we identify FBXO2 as a key modulator of amino acid-dependent mTORC1 signaling. Mechanistically, FBXO2 colocalizes and directly interacts with KPTN via its F-box-associated domain, promoting K48- and K63-linked polyubiquitination of KPTN at lysine residues 49, 67, 262, and 265. FBXO2-mediated KPTN ubiquitination disrupts its interaction with ITFG2 and SZT2, while enhancing its interaction with C12orf66, thereby impairing the ability of KICSTOR to recruit the GATOR1 complex to the lysosomal surface. Notably, FBXO2 protein levels are substantially upregulated in liver cancer patients and FBXO2-mediated KPTN ubiquitination facilitates the progression of hepatocellular carcinoma (HCC). These results reveal a key regulatory mechanism of the mTORC1 signaling and highlight FBXO2 and KPTN ubiquitination as therapeutic targets for HCC treatment.
    Keywords:  Cell biology; Liver cancer; Oncology; Signal transduction; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI195031
  6. Nat Protoc. 2025 Dec 19.
    CRISPR screens in human neural organoids and assembloids.
    Xiangling Meng, Noah Reis, Michael C Bassik, Sergiu P Pașca.
      Studying the molecular mechanisms underlying the assembly of the human nervous system remains a significant challenge. The ability to generate neural cells from pluripotent stem cells, combined with advanced genome-editing techniques, provides unprecedented opportunities to uncover the biology of human neurodevelopment and disease. Organoids and assembloids enable the in vitro modeling of previously inaccessible developmental processes, such as the specification and migration of human neurons, including the integration of cortical interneurons from the ventral into the dorsal forebrain. Here, we present a detailed protocol that combines pooled CRISPR-Cas9 screening with neural organoid and assembloid models and illustrate how it can be applied to map hundreds of disease genes onto cellular pathways and specific aspects of human neural development. Our protocol outlines key steps, from planning and optimizing genetic perturbations to designing readouts for neuronal generation and migration, conducting the screening and validating candidate genes. The screening experiments take ~3 months to complete and require expertise in stem cell culture and neural differentiation, genetic engineering of human induced pluripotent stem cell lines, fluorescence-activated cell sorting and next-generation sequencing and analyses. The integration of genetic screening and human cellular models constitutes a powerful platform for investigating the mechanisms of human brain development and disease, paving the way for the discovery of novel therapeutics.
    DOI:  https://doi.org/10.1038/s41596-025-01299-6
  7. EMBO Rep. 2025 Dec 16.
    Apelin signaling acts as a molecular switch between endothelial and hematopoietic stem cell fates.
    Jean Eberlein, Nadja Groos, Navina Shrestha Duwal, Wade W Sugden, Trista E North, Christian S M Helker.
      Hematopoietic stem and progenitor cells (HSPCs) emerge from arterial endothelial cells (ECs) through a process termed endothelial-to-hematopoietic-transition (EHT), a process induced by paracrine signals and driven by a transcriptional cascade. Despite inductive signals being broadly received by ECs in the dorsal aorta (DA), only a subset of ECs undergoes EHT, while others maintain their vascular identity. The molecular mechanisms that determine this selective fate decision remain poorly understood. Here, we discover Apelin signaling as a critical regulator of cell fates in the DA, acting as a molecular switch to balance vascular and hematopoietic identities. We show that Apelin receptor (Aplnr)-expressing ECs retain their arterial identity, while Aplnr non-expressing ECs are primed to become hemogenic endothelial cells (HECs) and transition into HSPCs. Loss of Apelin signaling leads to excessive EC-to-HEC conversion and increased HSPC numbers. Conversely, forced Aplnr expression abolishes HSPC formation by maintaining EC identity. These findings reveal that Apelin signaling regulates HSPC formation by preserving endothelial identity. In summary, our findings establish Apelin signaling as a critical regulator for balancing endothelial and hematopoietic fates.
    Keywords:  Apelin Signaling; Endothelial-to-hematopoietic Transition; Hematopoietic Stem Cells; Hemogenic Endothelium; Zebrafish
    DOI:  https://doi.org/10.1038/s44319-025-00656-6
  8. Nat Commun. 2025 Dec 13.
    PhotoFiTT: a quantitative framework for assessing phototoxicity in live-cell microscopy experiments.
    Mario Del Rosario, Estibaliz Gómez-de-Mariscal, Leonor Morgado, Raquel Portela, Guillaume Jacquemet, Pedro M Pereira, Ricardo Henriques.
      Phototoxicity in live-cell fluorescence microscopy can compromise experimental outcomes, yet quantitative methods to assess its impact remain limited. Here, we present PhotoFiTT (Phototoxicity Fitness Time Trial), an integrated framework combining a standardised experimental protocol with advanced image analysis to quantify light-induced cellular stress in label-free settings. PhotoFiTT leverages machine learning and cell cycle dynamics to analyse mitotic timing, cell size changes, and overall cellular activity in response to controlled light exposure. Using adherent mammalian cells, we demonstrate PhotoFiTT's ability to detect wavelength- and dose-dependent effects, showcasing that near-UV light induces significant mitotic delays at doses as low as 0.6 J/cm2, while longer wavelengths require higher doses for comparable deleterious effects. PhotoFiTT enables researchers to establish quantitative benchmarks for acceptable levels of photodamage, facilitating the optimisation of imaging protocols that balance image quality with sample health.
    DOI:  https://doi.org/10.1038/s41467-025-66209-6
  9. Nat Methods. 2025 Dec 15.
    Carta offers a computational approach to inference of differentiation maps from cell lineages.
      
    DOI:  https://doi.org/10.1038/s41592-025-02904-y
  10. Cell Commun Signal. 2025 Dec 19.
    Host PI3K inhibition via anti-cancer drug alpelisib influences Influenza A non-infectious particles and deletion-containing viral genomes.
    Ilechukwu Agu, Ivy José, Abhineet Ram, Daniel P Oberbauer, John G Albeck, Samuel L Díaz-Muñoz.
      RNA viruses can generate "defective" viral genomes during replication, which can interact with standard viral genomes affecting the course of infections. These non-standard viral genomes are related to milder clinical outcomes and are currently being tested as antivirals. Decades of research in influenza have focused on viral mechanisms affecting the production of deletion-containing viral genomes (DelVGs). Based on adaptations of influenza NS1 protein to manipulate host cell metabolism, we hypothesized host metabolic state could also alter the quantity and pattern of deletion-containing viral genomes and the particles that house them. To test this hypothesis, we manipulated host cell anabolic signaling activity and monitored the production of DelVGs and non-infectious particles by two influenza strains, using single-cell immunofluorescence and third-generation sequencing. We show that: 1) influenza infection activates PI3K signaling, with the A/H1N1 strain having roughly double the pAKT levels in single cells as the A/H3N2; 2) alpelisib, a PI3K receptor inhibitor, subverted the ability of both influenza strains to activate PI3K in a dose dependent manner; 3) DelVGs were increased roughly tenfold in polymerase complex segments and ~ 60% in the hemagglutinin segment of A/H1N1 at 20uM of alpelisib; and 4) the A/H3N2 strain did not show changes in DelVG production, but had a modest, statistically significant maximum increase of 11% in non-infectious particles. We find that host cell metabolism can increase the production of non-infectious particles and DelVGs during single rounds of infection, shifting potential interactions among virions. The differential results according to strain and alpelisib concentration suggest future directions examining strain differences in the NS1::p85β virus-host interaction and the specific metabolic state of the cell. Our study presents a new line of investigation into metabolic states associated with less severe flu infection and opens the possibility for potential induction of these states with metabolic drugs.
    DOI:  https://doi.org/10.1186/s12964-025-02598-x
  11. Nat Methods. 2025 Dec 18.
    SpaceBar enables single-cell-resolution clone tracing with imaging-based spatial transcriptomics.
    Grant Kinsler, Caitlin Fagan, Haiyin Li, Jessica Kaster, Maggie Dunne, Robert J Vander Velde, Ryan H Boe, Sydney Shaffer, Meenhard Herlyn, Arjun Raj, Yael Heyman.
      Imaging-based spatial transcriptomics methods allow for the measurement of spatial determinants of cellular phenotypes but are incompatible with random barcode-based clone-tracing methods, preventing the simultaneous detection of clonal and spatial drivers. Here we report SpaceBar, which enables simultaneous clone tracing and spatial gene expression profiling with standard imaging-based spatial transcriptomics pipelines. Our approach uses a library of 96 synthetic barcode sequences that combinatorially labels each cell. Thus, SpaceBar can distinguish between clonal dynamics and environmentally driven transcriptional regulation in complex tissue contexts.
    DOI:  https://doi.org/10.1038/s41592-025-02968-w
  12. FEBS Lett. 2025 Dec 17.
    The power of five - inositol polyphosphate 5-phosphatase gene mutations at the intersection of development and disease.
    Meagan J McGrath, Elizabeth M Davies, Lisa M Ooms, Randini Nanayakkara, Rajendra Gurung, Emily I Jones, Christina A Mitchell.
      Phosphoinositides are transient signaling lipids, derived from the reversible phosphorylation of phosphatidylinositol on intracellular membranes, which serve as master regulators of many essential cellular functions. Seven distinct phosphoinositide species require precise spatiotemporal control, which is regulated by specific phosphatidylinositol kinases and phosphatases. Here, we review one such family, the inositol polyphosphate 5-phosphatases, which comprise 10 mammalian enzymes that dephosphorylate the 5-position phosphate group from the inositol head group of PtdIns(4,5)P2, PtdIns(3,5)P2, and/or PtdIns(3,4,5)P3. Despite overlapping substrate specificities, the 5-phosphatases play nonredundant roles, including in development, as demonstrated by murine and zebrafish knockout studies. Mutations in several 5-phosphatase family members are associated with multisystem developmental and congenital syndromes. Associations between 5-phosphatase gene variants and diabetes and metabolic syndrome, neurodegenerative disease, and in rare cases cancer, are also emerging. Here, we provide a comprehensive discussion of the latest advances in this field, including updates on disease modeling and mechanisms.
    Keywords:  angiogenesis; autophagy; bone; cancer; cilia; endoplasmic reticulum; inositol polyphosphate 5‐phosphatase; metabolism; phosphoinositide; skeletal muscle
    DOI:  https://doi.org/10.1002/1873-3468.70247
  13. Nat Methods. 2025 Dec 15.
    MultiCell: geometric learning in multicellular development.
    Haiqian Yang, George Roy, Anh Q Nguyen, Dapeng Bi, Tomer Stern, Markus J Buehler, Ming Guo.
      During developmental processes such as embryogenesis, how a group of cells self-organizes into specific structures is a central question in biology. However, it remains a major challenge to understand and predict the behavior of every cell within the living tissue over time during such intricate processes. Here we present MultiCell, a geometric deep learning method that can accurately capture the highly convoluted interactions among cells. We demonstrate that multicellular data can be represented with both granular and foam-like physical pictures through a unified graph data structure, considering both cellular interactions and cell junction networks. Using this method, we achieve interpretable four-dimensional morphological sequence alignment and predict single-cell behaviors before they occur at single-cell resolution during Drosophila embryogenesis. Furthermore, using neural activation map and model ablation studies, we demonstrate that cell geometry and cell junction networks are essential features for predicting cell behaviors during morphogenesis. This method sets the stage for data-driven quantitative studies of dynamic multicellular developmental processes at single-cell precision, offering a proof-of-concept pathway toward a unified morphodynamic atlas.
    DOI:  https://doi.org/10.1038/s41592-025-02983-x
  14. Nat Commun. 2025 Dec 13.
    Evaluating transportability of in vitro cellular models to in vivo human phenotypes using gene perturbation data.
    Laurence J Howe, Yurii S Aulchenko, George Davey Smith, Neil M Davies, Jorge Esparza-Gordillo, Toby Johnson, Jimmy Z Liu, Tom G Richardson, Philippe Sanseau, Robert A Scott, Daniel D Seaton, Ashwini Sharma, Adrian Cortes.
      Gene perturbation screens (e.g. CRISPR-Cas9) assess the impact of gene disruption on in-vitro cellular phenotypes (e.g., proliferation, anti-viral response). In-vitro experiments can be useful models for in-vivo (organismal) phenotypes (e.g., immune cell anti-viral response and infectious diseases). However, assessing whether an in-vitro cellular model effectively captures in-vivo biology is challenging. An in-vitro model is 'transportable' to an in-vivo phenotype if perturbations impacting the in-vitro phenotype also impact the in-vivo phenotype with mechanism-consistent directionality and effect sizes. We propose a framework; Gene Perturbation Analysis for Transportability (GPAT), to assess model transportability using gene perturbation effect estimates from perturbation screens (in-vitro) and loss-of-function burden tests (in-vivo). In hypothesis-driven analyses, GPAT provides evidence for model transportability of higher lysosomal cholesterol accumulation in-vitro to lower human plasma LDL-cholesterol (P = 0.0006), consistent with the known role of lysosomes in lipid biosynthesis. In contrast, there was limited evidence for other putative in-vitro models. In hypothesis-free analyses, we find evidence for transportability of cancer cell line proliferation to in-vivo human plasma cellular phenotypes (e.g. erythroleukemia proliferation and plasma lymphocyte percentage). Here we show that perturbation data can be used to evaluate transportability of in-vitro cellular models, informing assay prioritisation and supporting novel hypothesis generation.
    DOI:  https://doi.org/10.1038/s41467-025-67199-1
  15. Nat Commun. 2025 Dec 16.
    Concurrent PIK3CA mutant promotes cachexia through inflammatory signaling in EGFR mutant lung cancer.
    Meiting Yue, Zhen Qin, Shijie Tang, Xinlei Cai, Yikai Zhao, Chen Yang, Liang Chen, Luonan Chen, Hongbin Ji.
      PIK3CA mutation is frequently concurrent with known oncogenic drivers such as EGFR mutation in lung cancer, raising an interesting question about its real function. Cachexia is a systemic disease arising from tumor-organ crosstalk, significantly contributing to cancer-related mortality. Through integrative study of genetically engineered mouse models (GEMMs) and clinical data, we find concurrent PIK3CA mutant preferentially drives cachexia in EGFR-mutant lung cancer, promoting malignant progression instead of cancer initiation. PIK3CA mutant-mediated cachexia can be overcome by osimertinib (Osi) treatment in Osi-sensitive GEMM. In contrast, chemotherapy, routinely used in clinic for those relapsed from Osi therapy, fails to ameliorate cachexia in Osi-resistant GEMM despite notable tumor suppression. PIK3CA mutant-driven cachexia is mediated through NF-κB activation and can be dampened by combined aspirin treatment. This work provides insights into PIK3CA mutant biological function and mechanisms behind its clinical impacts, and proposes a potential strategy for clinical management.
    DOI:  https://doi.org/10.1038/s41467-025-67345-9
  16. Elife. 2025 Dec 16. pii: RP103705. [Epub ahead of print]13
    The fate of pyruvate dictates cell growth by modulating cellular redox potential.
    Ashish G Toshniwal, Geanette Lam, Alex J Bott, Ahmad A Cluntun, Rachel Skabelund, Hyuck-Jin Nam, Dona R Wisidagama, Carl S Thummel, Jared Rutter.
      Pyruvate occupies a central node in carbohydrate metabolism such that how it is produced and consumed can optimize a cell for energy production or biosynthetic capacity. This has been primarily studied in proliferating cells, but observations from the post-mitotic Drosophila fat body led us to hypothesize that pyruvate fate might dictate the rapid cell growth observed in this organ during development. Indeed, we demonstrate that augmented mitochondrial pyruvate import prevented cell growth in fat body cells in vivo as well as in cultured mammalian hepatocytes and human hepatocyte-derived cells in vitro. We hypothesize that this effect on cell size was caused by an increase in the NADH/NAD+ ratio, which rewired metabolism toward gluconeogenesis and suppressed the biomass-supporting glycolytic pathway. Amino acid synthesis was decreased, and the resulting loss of protein synthesis prevented cell growth. Surprisingly, this all occurred in the face of activated pro-growth signaling pathways, including mTORC1, Myc, and PI3K/Akt. These observations highlight the evolutionarily conserved role of pyruvate metabolism in setting the balance between energy extraction and biomass production in specialized post-mitotic cells.
    Keywords:  D. melanogaster; cell biology; cell growth; genetics; hepatocytes; human; pyruvate metabolism; redox state; translation
    DOI:  https://doi.org/10.7554/eLife.103705
  17. bioRxiv. 2025 Dec 01. pii: 2025.11.28.691223. [Epub ahead of print]
    Development of Long-Term Human Adipocyte Organoids Manifesting Aging in Response to Intermittent Hypoxia.
    Yunzhou Dong, Jingjing Wang, Feifei Feng, Isra H Ali, Shahid Karim, Joshua Bock, Virend K Somers.
      Obstructive sleep apnea (OSA) (and consequent intermittent hypoxia (IH)) is increasingly recognized as a driver of adipose tissue dysfunction, insulin resistance, and aging. However, current in vitro experimental models inadequately capture the long-term effects of IH on human adipocytes. Here, we report the development and optimization of a robust long-term human adipocyte organoid culture system that faithfully recapitulates IH-induced adipocyte aging in vitro . Human stromal vascular fraction (SVF) cells, isolated from subcutaneous abdominal fat biopsies, were embedded in Matrigel and seeded into Biofloat U-bottom 96-well plates. Using a 1:1 Matrigel-cell mixture and optimized seeding volumes (5-20 µL), we established adipocyte organoids that formed within 10-12 days and remained viable with stable morphology for up to 90 days or more. Matrigel was essential for organoid integrity, while alternative matrices such as gelatin and low-melting agarose failed to support proper organoid formation. Subcutaneous preadipocyte medium with 10% FBS from ZenBio was superior to "Advanced/F12K" medium for adipogenic differentiation and long-term maintenance. To model OSA-related hypoxic stress, we exposed organoids to intermittent hypoxia using a programmable hypoxia chamber. IH treatment suppressed adipogenesis, as shown by reduced lipid accumulation, downregulation of adipogenic markers (e.g., PPARγ, adiponectin, FABP4), and smaller intracellular lipid droplets. Transmission electron microscopy (TEM) revealed IH-induced structural abnormalities, including ER fragmentation, mitochondrial disruption, nuclear enlargement, and heterochromatin formation, all of which are hallmarks of cellular aging. Furthermore, IH upregulated HIF1α, H2AX, and aging-associated histone methylation markers (H3K9me3, H3K79me3, H4K20me3), as well as extracellular matrix remodeling proteins such as fibronectin and LOX. Insulin signaling was also impaired, evidenced by decreased phosphorylation of PI3K and AKT. Collectively, these results establish a reliable platform for long-term human adipocyte organoid culture and demonstrate its utility in modeling IH-induced adipocyte dysfunction and aging. This system offers a physiologically relevant tool for mechanistic studies and preclinical therapeutic screening targeting hypoxia-related metabolic disorders.
    DOI:  https://doi.org/10.1101/2025.11.28.691223
  18. NPJ Syst Biol Appl. 2025 Dec 13.
    Challenges and opportunities for oncology drug repurposing informed by synthetic lethality.
    Michael Vermeulen, Andrew W Craig, Tomas Babak.
      Although two-thirds of cancers arise from loss-of-function mutations in tumor suppressor genes, there are few approved targeted therapies linked to these alterations. Synthetic lethality offers a promising strategy to treat such cancers by targeting vulnerabilities unique to cancer cells with these mutations. To identify clinically relevant synthetic lethal interactions, we analyzed genome-wide CRISPR/Cas9 knock-out (KO) viability screens from the Cancer Dependency Map and evaluated their clinical relevance in patient tumors through mutual exclusivity, a pattern indicative of synthetic lethality. Indeed, we found significant enrichment of mutual exclusivity for interactions involving cancer driver genes compared to non-driver mutations. To identify therapeutic opportunities, we integrated drug sensitivity data to identify inhibitors that mimic the effects of CRISPR-mediated KO. This approach revealed potential drug repurposing opportunities, including BRD2 inhibitors for bladder cancers with ARID1A mutations and SIN3A-mutated cell lines showing sensitivity to nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. However, we discovered that pharmacological inhibitors often fail to phenocopy KO of matched drug targets, with only a small fraction of drugs inducing similar effects. This discrepancy reveals fundamental differences between pharmacological and genetic perturbations, emphasizing the need for approaches that directly assess the interplay of loss-of-function mutations and drug activity in cancer models.
    DOI:  https://doi.org/10.1038/s41540-025-00618-7
  19. Nat Commun. 2025 Dec 15.
    Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.
    Tonci Ivanisevic, Yan Ma, Emiel Van Boxel, Wout Magits, Benoit Lechat, Zeynep Koçberber, Phillipp Willnow, Sarah-Maria Fendt, Greetje Vande Velde, Raj Sewduth, Anna A Sablina.
      Activating mutations in KRAS occur in approximately 30% of lung adenocarcinomas. Despite advances in RAS-targeted therapies, intrinsic resistance limits their long-term efficacy. Here, we identify elevated levels of wild-type KRAS (WT-KRAS) protein as a key driver of intrinsic resistance in KRAS-mutant lung tumors. KRAS accumulation results from impaired LZTR1-mediated degradation, triggered either by LZTR1 loss or pharmacological RAS inhibition. Stabilized WT-KRAS activates the mTOR/HIF1α pathway by promoting lysosomal recruitment of the SLC3A2/SLC7A5 amino acid transporter complex, reprogramming lysosomal amino acid sensing. Shallow deletions of LZTR1, present in up to 40% of KRAS-mutant lung adenocarcinomas, are associated with increased mTOR activity and may contribute to therapeutic resistance to RAS inhibitors. Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer.
    DOI:  https://doi.org/10.1038/s41467-025-67109-5
  20. Life Sci Alliance. 2026 Mar;pii: e202503526. [Epub ahead of print]9(3):
    Multi-omics analysis reveals metabolic diversity underlying endothelial cell functions.
    Stephan Durot, Peter F Doubleday, Lydia Schulla, Amélie Sabine, Tatiana V Petrova, Nicola Zamboni.
      Endothelial cells (ECs) line the vascular system and are key players in vascular homeostasis, yet their metabolic diversity across tissues, vascular beds, and growth states remains poorly understood. This study examines metabolic differences between proliferating and quiescent ECs and compares blood and lymphatic endothelium using proteomics and metabolomics. Our findings indicate that metabolism in quiescent ECs is not dormant but reorganized in a cell-specific manner, with decreased heme intermediates in human umbilical vein ECs and increased branched-chain amino acid catabolism across all quiescent ECs. Consistent with the differences identified in the omics data, perturbation studies revealed that inhibiting enzymes involved in heme, glutamate, fatty acid, and nucleotide biosynthesis led to distinct phenotypic responses in blood and lymphatic ECs. These findings highlight the importance of metabolic pathways in sustaining both proliferating and quiescent ECs and reveal how ECs from different vascular beds rely on distinct metabolic processes to maintain their functional states.
    DOI:  https://doi.org/10.26508/lsa.202503526
  21. Clin Transl Med. 2025 Dec;15(12): e70555
    The 'vulnerability code': Is cell identity the architect of its own decay?
    Dongsheng Bai, Zhenkun Cao, Chenxu Zhu.
      
    DOI:  https://doi.org/10.1002/ctm2.70555
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