bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–04–12
sixteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Clinicogenomic Landscape and Function of PIK3CA, AKT1, and PTEN Mutations in Breast Cancer.
  2. Preservation of Human Colonic Stem Cells Requires an ERK Dynamics Checkpoint Mediated by AKT.
  3. Generative machine learning unlocks the first proteome-wide image of human cells.
  4. Intracellular enzymatic reducing systems control receptor tyrosine kinase signaling via PTP1B.
  5. Lignature provides a curated resource of ligand induced transcriptomic signatures for signaling inference.
  6. QuantumXCT: Learning Interaction-Induced State Transformation in Cell-Cell Communication via Quantum Entanglement and Generative Modeling.
  7. Baseline cellular state dictates the molecular impact of KRAS mutant variants in pancreatic cancer cells.
  8. Temporal AI model predicts drivers of cell state trajectories across human aging.
  9. Flow-sensitive K + channels link flow to piezo1/PI3K/Akt1 pathway.
  10. Fatty acid scavenging enables cancer escape from KRAS inhibition.
  11. Ubiquitin ligase CHFR impairs Tie2 signaling via K 48 -linked ubiquitylation and degradation of Akt1 in endothelial cells.
  12. ERK-Mediated Phosphorylation of YAP Defines a Noncanonical FGF Signaling Mechanism in Stem Cells.
  13. Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
  14. Comparative single-cell atlases reveal injury-driven tubal epithelial regeneration as a window for ovarian carcinoma initiation.
  15. Metabolomics across scales: from single cells to population studies.
  16. Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses.
  1. JCO Precis Oncol. 2026 Apr;10(4): e2500609
    Clinicogenomic Landscape and Function of PIK3CA, AKT1, and PTEN Mutations in Breast Cancer.
    Jacqueline J Tao, Saumya D Sisoudiya, Hanna Tukachinsky, Alexa B Schrock, Ericka M Ebot, Smruthy Sivakumar, Ethan S Sokol, Neil Vasan.
       PURPOSE: To comprehensively characterize the clinical and genomic landscapes of PIK3CA, AKT1, and PTEN alterations and examine their functional and therapeutic implications in AKT-driven breast cancer.
    METHODS: Comprehensive genomic profiling of 51,767 breast tumors was performed using FoundationOne CDx or FoundationOne. We examined the genomic landscape of PIK3CA, AKT1, and PTEN alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data were used to functionally characterize clinical PTEN variants. Real-world clinical outcomes were assessed in patients treated with capivasertib plus fulvestrant.
    RESULTS: A total of 29,157 variants were identified across the three genes, including pathogenic variants and variants of uncertain significance. The most frequently altered gene was PIK3CA (37.4% of cases), followed by PTEN (13.5%) and AKT1 (5.4%). The most common alterations in each gene were PIK3CA H1047R (35.6% of PIK3CA-altered cases), E545K (19.7%), and E542K (11.7%); AKT1 E17K (69.7%); and PTEN homozygous copy number deletion (37.3%). PIK3CA alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), whereas AKT1 and PTEN alterations were balanced across ancestries. DMS data on missense PTEN mutations revealed that 32.5% showed discordant effects on protein stability and phosphatase activity. A subset of patients with rare AKT pathway variants derived meaningful progression-free survival and overall survival benefit from capivasertib.
    CONCLUSION: Here, we present the landscape of PIK3CA, AKT1, and PTEN alterations in, to our knowledge, the largest clinical cohort examined to date. The functional complexity of rare PTEN variants underscores the need for functional validation by tools such as DMS. Rare AKT pathway variants may predict clinical benefit from AKT inhibitors and warrant further clinical investigation.
    DOI:  https://doi.org/10.1200/PO-25-00609
  2. bioRxiv. 2026 Apr 05. pii: 2026.04.02.715982. [Epub ahead of print]
    Preservation of Human Colonic Stem Cells Requires an ERK Dynamics Checkpoint Mediated by AKT.
    Lauren Riede, Alexander Borowiec, Saptarshi Mallick, Sohini Mallick, Jayati Chakrabarti, Curtis A Thorne, Kelvin W Pond.
      Colonic stem cells reside in a microenvironment enriched in epidermal growth factor, which is essential for their survival and can activate both PI3K-AKT and MAPK-ERK pathways. This predicts co-activation of both pathways within the growth factor-high stem cell compartment at the base of crypts. However, in patient-derived human colonic organoids and normal human tissue, stem cells maintain robust AKT activity while suppressing ERK signaling despite active EGFR engagement. As stem cells differentiate, they activate pulsatile ERK signaling, which is essential for migration, survival, and maintenance of barrier function. We show that AKT-dependent phosphorylation of RAF-1 at serine 259 establishes a post-receptor checkpoint that maintains ERK temporal dynamics in stem cells. Acute activation of ERK in stem cells triggers rapid global differentiation. Disruption of the ERK checkpoint via mutation of serine 259 leads to sustained AKT and ERK co-activation in stem cells. Unlike ERK/AKT coactivation driven by apoptosis, co-activation in the stem cell compartment results in the emergence of a neoplastic, architecturally disorganized cell population dominating the cell fate profile. Incredibly, introducing brief ERK pulses through AKT inhibition or ERK activation triggers re-differentiation of neoplastic cells. Consistent with duration-dependent MAPK encoding principles, these data demonstrate that regardless of baseline signaling amplitude, that ERK signaling dynamics are epistatic to total kinase signaling load in human colonic stem cells.
    SIGNIFICANCE: Stem cells must balance self-renewal and differentiation while remaining responsive to continuous mitogenic stimulation to preserve tissue homeostasis. When self-renewal is impaired, wound healing and barrier integrity decline, whereas loss of proper differentiation drives tumorigenesis. Our findings demonstrate that this balance in the human colon is achieved through temporal control of kinase signaling rather than modulation of ligand availability. By establishing an AKT-dependent ERK dynamics checkpoint, colonic stem cells suppress differentiation-inducing ERK pulses while maintaining growth factor responsiveness. These results identify kinase dynamics as a fundamental determinant of epithelial homeostasis and suggest that subtle alterations in these dynamics may destabilize tissue organization during regeneration or chronic inflammation. Temporal encoding of kinase activity thus represents a central organizing principle in human stem cell biology.
    DOI:  https://doi.org/10.64898/2026.04.02.715982
  3. bioRxiv. 2026 Apr 02. pii: 2026.03.31.715748. [Epub ahead of print]
    Generative machine learning unlocks the first proteome-wide image of human cells.
    Huangqingbo Sun, Konstantin Kahnert, Jan N Hansen, William Leineweber, Mingyang Li, Wanyue Feng, Frederic Ballllosera, Ulrika Axelsson, Wei Ouyang, Emma Lundberg.
      The spatial organization of proteins within cells governs virtually all cellular functions. Yet, current imaging technologies can simultaneously visualize only tens of proteins, orders of magnitude below the thousands that populate a single human cell. Here, we present ProtiCelli , a deep generative model that simulates microscopy images for 12,800 human proteins from just three cellular landmark stains. Trained on 1.23 million images from the Human Protein Atlas, ProtiCelli outperforms existing methods in reconstruction accuracy and textural fidelity, and generalizes to unseen cell types and drug perturbations absent from training. We demonstrate that ProtiCelli -generated images preserve hierarchical subcellular organization, recapitulate known protein-protein interaction landscapes, and resolve compartment-specific functions of moonlighting proteins at the single-cell level. Remarkably, the model infers drug-induced changes in protein expression and localization from cell morphology alone, predicts cell cycle stage without dedicated cell cycle markers, and enables unsupervised segmentation of subcellular compartments as well as spatial decomposition of gene sets into functional regions. Ultimately, we leverage ProtiCelli to generate Proteome2Cell , an unprecedented dataset of 30.7 million simulated images creating 2,400 "virtual cells" across 12 human cell lines. These proteome-scale images enable the construction of hierarchical single-cell models that distinguish conserved from dynamic protein architectures. Integration of Proteome2Cell into the Human Protein Atlas democratizes the exploration of these "virtual cells". By computationally bridging the experimental scalability gap, ProtiCelli establishes a foundation for spatial virtual cell modeling and paves an avenue for transforming spatial proteomics from cataloging proteins to simulating complete cellular systems.
    DOI:  https://doi.org/10.64898/2026.03.31.715748
  4. Sci Adv. 2026 Apr 10. 12(15): eadv5362
    Intracellular enzymatic reducing systems control receptor tyrosine kinase signaling via PTP1B.
    Lucia Coppo, Wenchao Zhao, Qing Cheng, Axel Tobias Scholz, Elias S J Arnér, Markus Dagnell.
      Protein tyrosine phosphatases (PTPs) counteract receptor tyrosine kinase (RTK) signaling. Inhibition of PTPs by oxidation can be reversed by cytosolic thioredoxin (TXN), but less is known about regulation of PTPs by glutathione (GSH)-driven glutaredoxins (GLRXs). Here, we thus assessed GLRX1, GLRX2, and/or TXN1 in regulation of CO2/bicarbonate- and H2O2-mediated oxidation of the physiologically important PTP1B. GLRXs and TXN1 synergistically maintained PTP1B activity, and modulating cellular levels of either GLRX1, GLRX2, or TXN1 gave strong effects on phosphorylation cascades triggered by epidermal growth factor (EGF) or platelet-derived growth factor (PDGF). Furthermore, transient intracellular interactions of PTP1B with GLRX1, GLRX2, and TXN1 were discovered within minutes after stimuli with either PDGF or EGF, coinciding with control of the corresponding RTK-driven phosphorylation cascades. We conclude that TXN1 and GLRXs are key regulators of PTP1B activity and thus control cellular responses to RTK stimulation.
    DOI:  https://doi.org/10.1126/sciadv.adv5362
  5. Genome Res. 2026 Apr 08. pii: gr.281287.125. [Epub ahead of print]
    Lignature provides a curated resource of ligand induced transcriptomic signatures for signaling inference.
    Ying Xin, Md Amanullah, Cheng Qian, Chingmo Zhou, Jiang Qian.
      Ligand-receptor interactions mediate intercellular communication, inducing transcriptional changes that regulate physiological and pathological processes. Ligand-induced transcriptomic signatures can be used to infer ligand activity; however, the absence of a comprehensive set of ligand-response signatures has limited their practical application in predicting ligand-receptor interactions. To bridge this gap, we develop Lignature, a curated database encompassing intracellular transcriptomic signatures for 362 human ligands, significantly expanding the repertoire of ligands with available intracellular response signatures such as CytoSig and ImmuneDictionary. Lignature compiles signatures from published transcriptomic datasets, generating both gene- and pathway-based signatures for each ligand. We apply Lignature to prioritize ligand-associated transcriptional activity in controlled in vitro experiments and real-world single-cell sequencing datasets. Across these settings, Lignature consistently improves the prioritization of experimentally supported ligands compared with existing approaches. We additionally develop a regression-based framework to model combinatorial regulation by multiple ligands. These results establish Lignature as a robust platform for ligand signaling inference, providing a powerful tool to explore ligand-receptor interactions across diverse experimental and physiological contexts.
    DOI:  https://doi.org/10.1101/gr.281287.125
  6. ArXiv. 2026 Apr 02. pii: arXiv:2604.02203v1. [Epub ahead of print]
    QuantumXCT: Learning Interaction-Induced State Transformation in Cell-Cell Communication via Quantum Entanglement and Generative Modeling.
    Selim Romero, Shreyan Gupta, Robert S Chapkin, James J Cai.
      Inferring cell-cell communication (CCC) from single-cell transcriptomics remains fundamentally limited by reliance on curated ligand-receptor databases, which primarily capture co-expression rather than the system-level effects of signaling on cellular states. Here, we introduce QuantumXCT, a hybrid quantum-classical generative framework that reframes CCC as the problem of learning interaction-induced state transformations between cellular state distributions. By encoding transcriptomic profiles into a high-dimensional Hilbert space, QuantumXCT trains parameterized quantum circuits to learn a unitary transformation that maps a baseline non-interacting cellular state to an interacting state. This approach enables the discovery of communication-driven changes in cellular state distributions without requiring prior biological assumptions. We validate QuantumXCT using both synthetic data with known ground-truth interactions and single-cell RNA-seq data from ovarian cancer-fibroblast co-culture systems. The model accurately recovers complex regulatory dependencies, including feedback structures, and identifies dominant communication hubs such as the PDGFB-PDGFRB-STAT3 axis. Importantly, the learned quantum circuit is interpretable: its entangling topology can be translated into biologically meaningful interaction networks, while post hoc contribution analysis quantifies the relative influence of individual interactions on the observed state transitions. By shifting CCC inference from static interaction lookup to learning data-driven state transformations, QuantumXCT provides a generative framework for modeling intercellular communication. This work establishes a new paradigm for de novo discovery of communication programs in complex biological systems and highlights the potential of quantum machine learning in single-cell biology.
  7. bioRxiv. 2026 Mar 12. pii: 2026.03.10.710185. [Epub ahead of print]
    Baseline cellular state dictates the molecular impact of KRAS mutant variants in pancreatic cancer cells.
    Yanixa Quiñones-Avilés, Barbora Salovska, Cassandra S Markham, Yi Di, Benjamin E Turk, Yansheng Liu, Mandar Deepak Muzumdar.
      KRAS is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), where hotspot alterations in codons 12, 13, and 61 drive tumor initiation and progression. Although distinct biochemical properties have been described for individual KRAS mutants, whether they generate unique allele-specific signaling programs in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants in reconstituted isogenic, KRAS-deficient PDAC cell lines by integrated transcriptomic, proteomic, and phosphoproteomic profiling. We found that baseline cellular state, rather than allele identity, was the predominant driver of molecular variation. Comparisons with established KRAS reference signatures revealed significant but moderate overlap at the mRNA level and less so at the proteome level. Pathway analyses highlighted interferon response and mitochondrial translation as recurrently altered across alleles, while phosphoproteomic data confirmed robust ERK1/2 activity and suppression of DYRK kinase substrates by mutant KRAS expression. Importantly, no robust allele-specific molecular programs were identified. Together, our study establishes a comprehensive multi-omics resource for KRAS signaling in PDAC and demonstrates that cellular context exerts a stronger influence than allele identity in shaping molecular profiles, with implications for interpreting putative allele-specific signaling dependencies and therapeutic vulnerabilities.
    DOI:  https://doi.org/10.64898/2026.03.10.710185
  8. bioRxiv. 2026 Apr 01. pii: 2026.03.30.715396. [Epub ahead of print]
    Temporal AI model predicts drivers of cell state trajectories across human aging.
    Javier Gόmez Ortega, Rangarajan D Nadadur, Akira Kunitomi, Steven Kothen-Hill, Julian U G Wagner, Sarp D Kurtoglu, Bumjoon Kim, Madigan M Reid, Thomas Lu, Kaho Washizu, Lukas Zanders, Han Chen, Yujie Zhang, Sarah Ancheta, Sara Lichtarge, William A Johnson, Chris Thompson, Dereck M Phan, Alexis J Combes, Andrew C Yang, Neha Tadimeti, Stefanie Dimmeler, Shinya Yamanaka, Michael Alexanian, Christina V Theodoris.
      Foundational AI models have recently shown promise for predicting the impact of perturbations on cell states. However, current models typically consider only one cell state at a time, limiting their ability to learn how cellular responses unfold over time, particularly across long trajectories such as diseases of aging. Here, we develop a temporal AI model, MaxToki, trained on nearly 1 trillion gene tokens including cell state trajectories across the human lifespan to generate cell states across long timelapses of human aging. MaxToki generalized to unseen trajectories through in-context learning and predicted novel age-modulating targets that were experimentally verified to influence age-related gene programs and functional decline in vivo. MaxToki represents a promising strategy for temporal modeling to accelerate the discovery of interventions for programming therapeutic cellular trajectories.
    DOI:  https://doi.org/10.64898/2026.03.30.715396
  9. bioRxiv. 2026 Mar 12. pii: 2026.03.10.710828. [Epub ahead of print]
    Flow-sensitive K + channels link flow to piezo1/PI3K/Akt1 pathway.
    Sang Joon Ahn, Katie Beverley, Sara T Granados, Man Long Kwok, Jiwang Chen, Yulia Komarova, Ibra S Fancher, Shane A Phillips, Irena Levitan.
       Background: Endothelial response to flow is key to vascular function in health and disease. Our earlier studies demonstrated that endothelial Kir2.1 is essential for flow-induced Akt1/eNOS signaling and for flow-induced vasodilation (FIV) but the mechanistic integration between Kir and other flow signaling pathways remained poorly understood.
    Methods: We use a combination of electrophysiological recordings in real time of flow exposure, Ca 2+ imaging, pressure myography of resistance arteries, and echocardiography.
    Results: We demonstrate that Kir2.1 is essential for flow-induced PI3K phosphorylation, whereas expression of myristoylated Akt1, which bypasses PI3K-dependent membrane recruitment, restores flow-induced Akt1/eNOS phosphorylation in Kir2.1-deficient endothelium. It also restores FIV in Kir2.1-deficient mesenteric arteries. We further demonstrate that Kir2.1 is essential for flow-induced Ca²⁺ influx mediated by Piezo1 and TRPV4 channels, whereas Ca²⁺ influx induced by pharmacological activation of these channels is Kir2.1 independent. Deficiency of Piezo1 does not affect endothelial Kir2.1 channels. We also discover that flow activation of endothelial Kir2.1 requires Syndecan1, thus creating a link between glycocalyx and downstream effects. Physiologically, we find that endothelial Kir2.1 is suppressed by infusion of Angiotensin-II and by advanced aging, resulting in significant impairment of FIV. In both cases, FIV is fully restored by endothelium-specific over-expression of Kir2.1.
    Conclusions: Our study reveals that Kir2.1 serves as a mechanistic linker between endothelial glycocalyx to Piezo1-mediated Ca 2+ influx and downstream signaling suggesting a new integrated model of endothelial mechanotransduction. A functional loss of endothelial Kir2.1 is shown to play a significant role in FIV impairment in Angiotensin-induced hypertension and aging.
    DOI:  https://doi.org/10.64898/2026.03.10.710828
  10. bioRxiv. 2026 Apr 03. pii: 2026.04.01.715565. [Epub ahead of print]
    Fatty acid scavenging enables cancer escape from KRAS inhibition.
    Zihang Yuan, Bo Lin, Chunlan Wang, Yingying Miao, Da Zhang, Ziru Meng, Gangqi Wang, Andrew M Lowy, Michael Karin, Fei Yang, Beicheng Sun, Hua Su.
      Although inhibitors of oncogenic KRAS have shown clinical efficacy 1 , resistance to KRAS inhibition is common 2 , and its molecular basis remains unclear. Here we show that KRASi-resistant cancer cells sustain mitochondrial bioenergetics through enhanced fatty acid (FA) metabolism, despite suppression of canonical KRAS signaling. Specifically, KRASi-resistant pancreatic cancer cells exploit macropinocytosis to scavenge FA released from adipose tissue, fueling beta-oxidation independently of KRAS-PI3Kα signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3Kγ-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3Kγ signaling dismantles this metabolic program and restores KRASi sensitivity. This pathway operates across multiple KRAS-mutated cancers and is associated with poor therapeutic response and outcome. These findings offer a promising strategy for overcoming KRASi resistance.
    DOI:  https://doi.org/10.64898/2026.04.01.715565
  11. bioRxiv. 2026 Mar 31. pii: 2026.03.31.715582. [Epub ahead of print]
    Ubiquitin ligase CHFR impairs Tie2 signaling via K 48 -linked ubiquitylation and degradation of Akt1 in endothelial cells.
    Mohammad Owais Ansari, Gary C H Mo, Lasanthi Jayathilaka, Hui Chen, Asrar B Malik, Chinnaswamy Tiruppathi.
      Vascular endothelial (VE)-cadherin is essential for maintaining endothelial junctional barrier integrity. The Angiopoietin-1 (Ang-1)/Tie2 axis induced Akt1 activation is crucial for maintaining endothelial junctional barrier by inhibiting FoxO1 and suppressing expression of Angiopoietin-2 (Ang-2), a Tie2 antagonist. Systemic inflammatory conditions such as sepsis, Akt1 expression is reduced, whereas FoxO1-dependent Ang-2 expression is increased, resulting in endothelial barrier dysfunction. We previously showed that the TLR4/FoxO1 axis induces the ubiquitin E3 ligase CHFR, which promotes endothelial barrier disruption by targeting VE-cadherin for ubiquitylation and degradation. However, little is known about Akt1 expression during vascular inflammation. Here, we identified FoxO1-dependent CHFR expression as a key mechanism driving K48-linked polyubiquitylation and proteasomal degradation of Akt1 in endothelial cells (EC). LPS-induced K 48 -linked ubiquitylation of Akt1 was prevented in CHFR-depleted human EC and in endothelial-specific Chfr knockout ( Chfr ΔEC ) mice. Accordingly, CHFR depletion increased Akt1 and VE-cadherin expression in both human lung EC and Chfr ΔEC mice. Chfr ΔEC mouse lungs also exhibited elevated Ang-1 and Tie2 expression, and Ang-1 stimulation induced sustained Akt1 phosphorylation in CHFR-deficient EC. Moreover, CHFR depletion prevented LPS-induced expression of FoxO1 and Ang-2 in EC. Mechanistically, CHFR interacted with phosphorylated Akt1 and mediated its ubiquitylation at lysine residues K30, K39, K154, and K268. Expression of a ubiquitylation-deficient Akt1 mutant prevented LPS-induced VE-cadherin degradation and vascular injury. Collectively, these findings identify CHFR as a critical regulator of endothelial inflammatory responses by controlling Akt1 stability and VE-cadherin expression during inflammation.
    DOI:  https://doi.org/10.64898/2026.03.31.715582
  12. Adv Sci (Weinh). 2026 Apr 10. e11484
    ERK-Mediated Phosphorylation of YAP Defines a Noncanonical FGF Signaling Mechanism in Stem Cells.
    Xiaolei Zhao, Shannon Erhardt, Li Tang, Xiaotong Chen, Stephen M Farmer, Zixiu Cheng, Wen Chen, Ella Ziyuan Lu, Kihan Sung, Chang-Ru Tsai, Mingjie Zheng, Sheng Zhang, Yang Liu, Jianxin Wang, Min Li, James F Martin, Jun Wang.
      While Fgf and Hippo-Yap signaling are fundamental for proper development, homeostasis, and disease, their crosstalk remains largely unknown. Here, we identified that Yap and Taz, canonical Hippo effectors, function as noncanonical effectors of Fgf signaling to maintain the proper function of neural crest (NC) lineages. NC cells are a multipotent stem cell population during vertebrate embryogenesis that contribute to numerous structures and diverse cell lineages, including craniofacial and cardiac tissues, neurons, and suture mesenchymal cells (SMCs), a specified cell population required for cranial bone growth and repair. We observed that activation of Fgf signaling in NC cells and NC-derived SMCs inhibited osteogenesis while simultaneously enhancing stemness and proliferation. Interestingly, these effects were reversed by inhibition of either Yap/Taz or phosphorylated Erk1/2 (pErk1/2). Mechanistically, Fgf signaling promotes the interaction of Yap and pErk1/2, increasing the chromatin occupancy of Yap at genes regulating stemness, proliferation, and osteogenesis. We further show that pERK1/2 phosphorylates YAP at the noncanonical S128 site, enhancing YAP's nuclear localization. This mechanism is conserved across mouse and human cells and is active in Apert syndrome-associated FGF gain-of-function models, revealing a previously unrecognized FGF-YAP axis in stem cell regulation.
    Keywords:  ERK; FGF signaling; YAP; neural crest cell; suture mesenchymal cells
    DOI:  https://doi.org/10.1002/advs.202511484
  13. Circ Res. 2026 Apr 10. 138(8): e326982
    Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
    Gwang-Bum Im, Juan M Melero-Martin.
      Mitochondria are increasingly recognized as central regulators of vascular health, shaping endothelial cell function through roles that extend far beyond energy production. In addition to coordinating redox balance, calcium dynamics, and biosynthetic support, recent studies have revealed that mitochondria participate in intercellular communication, with evidence of transfer events emerging in vascular contexts. Parallel efforts have advanced the deliberate delivery of exogenous mitochondria from preclinical proof-of-principle studies to first-in-human trials, demonstrating that freshly isolated organelles can be harvested and administered in real-time to critically ill patients with favorable early outcomes. The mechanisms underlying these benefits remain incompletely defined, and strategies for efficient and scalable delivery are still emerging. In this review, we prioritize recent evidence linking mitochondrial function to endothelial cell physiology, highlight the nascent but growing field of mitochondrial transfer in the vasculature, and examine how mitochondrial transplantation is evolving from experimental concept to clinical translation. Together, these advances point to new therapeutic avenues for preserving vascular integrity and treating disease.
    Keywords:  cell communication; endothelial cells; mitochondria; regenerative medicine; therapeutics
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326982
  14. bioRxiv. 2026 Mar 30. pii: 2026.03.26.714557. [Epub ahead of print]
    Comparative single-cell atlases reveal injury-driven tubal epithelial regeneration as a window for ovarian carcinoma initiation.
    Coulter Q Ralston, Andrea Flesken-Nikitin, Dah-Jiun Fu, Christopher S Ashe, Blaine A Harlan, Md Mozammal Hossain, Derek K Wang, Anna Yemelyanova, Elisa Schmoeckel, Andrew K Godwin, Doris Mayr, Benjamin D Cosgrove, Alexander Yu Nikitin.
      High-grade serous carcinoma (HGSC), the most lethal form of ovarian cancer, preferentially originates in the tubal epithelium (TE) of the distal uterine tube (also known as Fallopian tube or oviduct). Mouse models are widely used to study how HGSC initiates in humans; however, the extent to which mouse and human uterine tubes are comparable remains unclear. Here, we conduct cross-species single-cell transcriptomic comparative analyses and organoid assay validations to reveal conserved differentiation trajectories from bipotent progenitors to secretory or ciliated cell fates. Regional analyses of both datasets reveal enriched injury repair features in the distal human TE, where mice lack such a trend. Experimentally inducing mechanical injury to the mouse TE yields significant expansion of pre-ciliated cells compared to uninjured counterparts. Furthermore, inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, in regenerating pre-ciliated cells leads to rapid neoplastic transformation, implicating post-traumatic repair as a permissive window for malignant transformation. Together, our findings establish a comparative atlas of cell states between mice and humans, show that injury-associated regeneration may contribute to the known vulnerability of the fimbrial region, and raise potential concerns regarding procedures or conditions that mechanically perturb the tubal epithelium.
    DOI:  https://doi.org/10.64898/2026.03.26.714557
  15. Nature. 2026 04;652(8109): 313-320
    Metabolomics across scales: from single cells to population studies.
    Theodore Alexandrov, Nicola Zamboni.
      Metabolomics has matured into a powerful approach for probing metabolism, offering readouts that closely reflect cellular and organismal function in health and disease. Here we highlight two rapidly advancing frontiers: single-cell metabolomics and population-scale metabolomics. Single-cell metabolomics resolves the metabolic states of individual cells, uncovering cell-to-cell heterogeneity and spatial organization within tissues. Population-scale profiling profiles metabolites across large cohorts, enabling the discovery of markers of disease, environmental exposures and genetic variation. Although these approaches operate at different scales, they face shared challenges-including metabolite identification, quantification and multimodal data integration-and offer common advantages, such as the ability to capture non-genetic influences on phenotype and to scale to high throughput. We propose that continued advances in scalability will bring these domains together, enabling the construction of comprehensive metabolic atlases that chart cellular and interindividual variation and provide training data for foundation models of metabolism. By integrating cellular and population-level insights, single-cell and population-scale metabolomics promise to advance our understanding of metabolism across biology, medicine and pharmacology.
    DOI:  https://doi.org/10.1038/s41586-026-10277-1
  16. Cell Death Differ. 2026 Apr 07.
    Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses.
    Patricia Wilson, Vishakha Vishwakarma, Rebecca Norcross, Kashmira Khaire, Van N Pham, Brant M Weinstein, Hyun Min Jung, Emilia Galperin.
      An interplay of growth factors and signaling pathways governs the development and maintenance of lymphatic vasculature, ensuring proper fluid homeostasis and immune function. Disruption of these regulatory mechanisms can lead to congenital lymphatic disorders and contribute to various pathological conditions. However, the mechanisms underlying the molecular regulation of these processes remain elusive. Here, we reveal a critical and previously unappreciated role for the signaling scaffold protein Shoc2 in lymphangiogenesis. We demonstrate that loss of Shoc2 results in near-complete loss of lymphatic vasculature in vivo and senescence of lymphatic endothelial cells in vitro. Mechanistically, Shoc2 is required for balancing signaling through the ERK1/2 pathway, and its loss results in increased mTORC1 signaling. This dysregulation impairs mitochondrial respiration and triggers an IRF/IFN-II response, ultimately leading to cellular senescence. Strikingly, expression of the Noonan Syndrome with Loose anagen Hair (NSLH)-causing Shoc2 variant S2G phenocopies the effects of Shoc2 loss. Together, these studies establish the critical role of Shoc2 in lymphangiogenesis and uncover a novel mechanistic link between Shoc2 signaling, mitochondrial function, innate immune response, and lymphatic development, with significant implications for Ras-pathway-related congenital disorders.
    DOI:  https://doi.org/10.1038/s41418-026-01730-9
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