bims-pideca 2026-04-19 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2026–04–19
fourteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Endocrine and metabolic features of PTEN hamartoma tumor syndrome in childhood: a pediatric case series.
mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway.
Structural basis for TORC2 activation.
Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.
Antagonistic Pleiotropy Governing Reproductive Aging: Evolutionary Regulation of Endometrial Receptivity.
Graded activation of the CLEAR network through mTORC1 suppression on cargo-harboring lysosomes.
Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
Loss of Hepatocyte PI3Kα Reduces Hepatocellular Carcinoma and Hepatocyte Proliferation in Association with Altered Lipid Metabolism.
Unveiling gene perturbation effects through gene regulatory networks inference from single-cell transcriptomic data.
Clonal biases dictate availability of colonic cancer driver mutations for transformation.
Identification of pathological CD133+ endothelial cells in venous malformations.
Aging changes cell mechanics and dynamics associated with cytoplasmic crowding.
Targeting the chromatin modifying enzyme, KDM5C, enhances AKT inhibition response in ER+ breast cancer.
Endothelial Cells as Active Lipid Gatekeepers: Vascular Control of Lipid Handling and Metabolic Homeostasis.

J Pediatr Endocrinol Metab. 2026 Apr 13.

Endocrine and metabolic features of PTEN hamartoma tumor syndrome in childhood: a pediatric case series.

Nazlı Sultan Özsoy, Ahmet Baştürk, Derya Altay, Leyla Kara, Ülkü Gül Şiraz, Nihal Hatipoğlu.

   OBJECTIVES: Phosphatase and tensin homolog (PTEN) Hamartoma Tumor Syndrome (PHTS) is caused by germline inactivating mutations in the PTEN gene and is phenotypically variable, often presenting diagnostic challenges and systemic complications during childhood.
CASE PRESENTATION: This case series presents four pediatric patients with confirmed PTEN mutations. The clinical features included juvenile polyposis, hypoglycemia, growth hormone deficiency, juvenile papillomatosis, thyroid nodules, cerebral cavernoma, and insulin resistance.
CONCLUSIONS: This report highlights the heterogeneous pediatric phenotype of PHTS and draws attention to the non-tumoral manifestations of PTEN mutations, including abnormalities in glucose metabolism, growth axis, and neurodevelopment. Early diagnosis and multidisciplinary follow-up are essential to prevent potential complications.

Keywords:  PTEN gene; cancer; hypoglycemia; juvenile polyposis

DOI:  https://doi.org/10.1515/jpem-2025-0587
Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00195-4. [Epub ahead of print]86(8): 1546-1559.e8

mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway.

Thomas A O'Loughlin, John S Stiles, Pritika Acharya, Abolfazl Arab, Laine Goudy, Raymond Dai, Ashir A Borah, William A Weiss, Uche N Medoh, Luke A Gilbert.

  Aberrant activation of the PI3K/AKT/mTOR signaling pathway is a common feature of cancer, but while mTOR kinase represents an attractive drug target, mTOR inhibitors have not seen broad success as single agents. To identify strategies to enhance the utility of third-generation bi-steric mTORC1 inhibitors, we performed genome-scale CRISPR interference chemogenomics screens, which revealed that mTORC1 inhibitor-mediated cytostasis leaves cells exquisitely dependent on the lipid peroxide scavenging enzyme GPX4. Mechanistically, using unbiased CRISPR activation chemogenomics screens, we demonstrate that mTORC1-dependent control of ferroptosis occurs, in part, through regulation of SCARB1 expression. Specifically, we find that the high-density lipoprotein (HDL) can suppress ferroptosis through interaction with its receptor SCARB1 and delivery of vitamin E to target cells. Our work highlights combining mTORC1 with GPX4 inhibition as one of the most promising combinatorial approaches for mTOR-targeted cancer therapies and defines an HDL-SCARB1 ferroptosis-suppression system that is regulated by mTORC1 activity.

Keywords:  GPX4; HDL; SCARB1; antioxidant; cancer; cell biology; ferroptosis; functional genomics; lipoprotein; mTOR; tocopherol; vitamin E

DOI:  https://doi.org/10.1016/j.molcel.2026.03.019
Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00198-X. [Epub ahead of print]86(8): 1560-1573.e5

Structural basis for TORC2 activation.

Luoming Zou, Maria G Tettamanti, Caroline Gabus, Ariane Bergmann, Robbie Loewith, Lucas Tafur.

  The target of rapamycin complex 2 (TORC2) is a central node in signaling feedback loops, serving to maintain the biophysical homeostasis of the plasma membrane (PM). How TORC2 is regulated by mechanical perturbation of the PM is not well understood. To address this, we determined the cryo-electron microscopy structure of endogenous yeast TORC2 at up to 2.2 Å resolution. Our model refines the position and interactions of TORC2-specific subunits, providing a structural basis for the differential assembly of Tor2 into TORC2. Furthermore, we observe the insertion of the pleckstrin-homology domain of the Avo1 subunit into the Tor2 active site, providing a regulatory mechanism mediated by phosphoinositides. Structure-guided functional experiments reveal a potential TORC2 membrane-binding surface and a positively charged pocket in the Avo3 subunit that is necessary for TORC2 activation. Collectively, our data suggest that signaling phosphoinositides activate TORC2 by membrane-induced structural rearrangements via the concerted action of conserved regulatory subunits.

Keywords:  TOR signaling; cell growth; cryo-electron microscopy; membrane mechanotransduction; phosphoinositides; target of rapamycin complex 2

DOI:  https://doi.org/10.1016/j.molcel.2026.03.022
Mol Cell Proteomics. 2026 Apr 15. pii: S1535-9476(26)00065-4. [Epub ahead of print] 101569

Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.

Colin Zenge, Brittany Q Pham, Kihong Nam, Elana Apfelbaum, Heeseon An, Alban Ordureau.

  Altered metabolism is a hallmark of cancer, making metabolic enzymes attractive therapeutic targets. However, metabolic inhibitors have shown limited clinical success, partly due to differences between standard culture media and physiological nutrient conditions. Human plasma-like medium (HPLM) better recapitulates in vivo metabolite concentrations, yet its effects on cellular proteomes remain poorly characterized. We performed comprehensive TMTpro-based quantitative proteomics and phosphoproteomics across nine cancer cell lines cultured in DMEM or HPLM, consistently quantifying over 10,000 proteins and 24,000 phosphorylation sites across all three biological replicates with high reproducibility. Physiological media induced profound cell-type-specific remodeling of metabolic networks, mitochondrial proteomes, and signaling pathways. While decreased mTORC1 and CDK activity represented universal responses across all cell lines, metabolic enzyme expression exhibited striking heterogeneity. Enzymes in folate metabolism and pyrimidine salvage pathways showed consistent reductions across all cell types, indicating that drug responses may vary with media choice. Mitochondrial proteome composition and morphology displayed cell-type-specific adaptations. Phosphoproteomic analysis revealed kinase signaling networks underlying these metabolic changes. This dataset, accessible via an interactive web application, provides a resource for metabolic research using physiological media, highlighting substantial cell-type-specific variability in how media affect proteomes and signaling pathways.

Keywords:  CDK activity; Cancer cell metabolism; Physiological Media; Proteomics; mTORC1 signaling

DOI:  https://doi.org/10.1016/j.mcpro.2026.101569
Reproduction. 2026 Apr 08. pii: xaag044. [Epub ahead of print]

Antagonistic Pleiotropy Governing Reproductive Aging: Evolutionary Regulation of Endometrial Receptivity.

Hiroshi Kobayashi, Miki Nishio, Mai Umetani, Hiroshi Shigetomi, Shogo Imanaka, Hiratsugu Hashimoto.

  This review aims to integrate current knowledge on how mTORC1-centered metabolic and stress-response pathways regulate endometrial decidualization, cellular senescence, and receptivity, with particular emphasis on their impact on implantation in advanced maternal age and metabolic disorders. A literature search was conducted using PubMed and Google Scholar without temporal restrictions, and studies were selected according to predefined inclusion and exclusion criteria focusing on metabolic signaling and reproductive function. Physiological mTORC1 activation during the proliferative phase supports stromal cell proliferation, protein synthesis, and initiation of decidualization, while facilitating formation and clearance of physiological senescent cells. Conversely, sustained mTORC1 activation associated with aging or metabolic dysfunction enhances cellular senescence and the senescence-associated secretory phenotype (SASP) through autophagy suppression, increased oxidative stress, and DNA damage, leading to impaired decidualization and reduced endometrial receptivity. This pattern aligns with the principle of antagonistic pleiotropy, whereby traits advantageous for reproduction in youth become detrimental to tissue function later. Dysregulation of mTORC1 and its related pathways-including AMPK, Tuberous Sclerosis Complex 2 (TSC2), and the p53 axis-is linked to implantation failure, particularly in advanced maternal age, obesity, and insulin resistance. In conclusion, mTORC1-centered metabolic and stress-response networks are fundamental regulators of endometrial maturation and senescence. Incorporating the assessment of mTORC1 activity and aging-associated markers may improve endometrial evaluation and reproductive outcomes, particularly in women of advanced reproductive age. Furthermore, such approaches may also enhance diagnostic precision and potentially increase success rates in assisted reproductive technologies (ART).

Keywords:  Aging; Antagonistic pleiotropy; Endometrium; Receptivity; mechanistic Target of Rapamycin (mTOR)

DOI:  https://doi.org/10.1093/reprod/xaag044
Cell Rep. 2026 Apr 09. pii: S2211-1247(26)00306-2. [Epub ahead of print]45(4): 117228

Graded activation of the CLEAR network through mTORC1 suppression on cargo-harboring lysosomes.

Cheng-Wei Hsieh, Guang-Chao Chen, Wei Yuan Yang.

  Cellular lysosomal capacity is tightly controlled to match catabolic demands and sustain lysosomal signaling pathways. Here, we report that cells can adjust their lysosomal capacity in response to varying autophagy loads. Manipulating the number of mitochondria targeted for mitophagy leads to a proportional upregulation of transcription factor EB (TFEB)-mediated lysosome adaptation programs. This quantitative control is exerted through Rag GTPase-driven mTORC1 suppression. GATOR1 is selectively recruited to lysosomes containing autophagic cargo, initiating local Rag GTPase-dependent suppression of mTORC1 activities. This mitophagy-induced mTORC1 suppression leads to TFEB activation and dephosphorylation of TOS-motif-containing substrates (S6K and 4EBP) under nutrient-rich conditions. This phenomenon similarly occurs during aggrephagy. These findings suggest that autophagic cargo-harboring lysosomes exhibit consistently low mTORC1 activity. Lysosomes can, therefore, sense the magnitude of autophagy loads and quantitatively translate this signal into TFEB activation to support self-regulated homeostasis.

Keywords:  CP: molecular biology; GATOR1; TFEB; aggregate autophagy; folliculin; lysosome; mTORC1; mitophagy

DOI:  https://doi.org/10.1016/j.celrep.2026.117228
Cell. 2026 Apr 15. pii: S0092-8674(26)00333-8. [Epub ahead of print]

Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.

José Reyes, Isabella Del Priore, Andrea C Chaikovsky, Nikhita Pasnuri, Ahmed M Elhossiny, Jin Park, Philipp Weiler, Tobias Krause, Andrew Moorman, Catherine Snopkowski, Meril Takizawa, Cassandra Burdziak, Nalin Ratnayeke, Ignas Masilionis, Yu-Jui Ho, Ronan Chaligné, Paul B Romesser, Aveline Filliol, Tal Nawy, John P Morris, Zhen Zhao, Marina Pasca Di Magliano, Direna Alonso-Curbelo, Dana Pe'er, Scott W Lowe.

  The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we developed for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.

Keywords:  KRAS inhibitors; benign-to-malignant transition; niche dynamics; p53; pancreatic cancer; single-cell biology; spatial transcriptomics; tumor initiation; tumor suppression

DOI:  https://doi.org/10.1016/j.cell.2026.03.032
JHEP Rep. 2026 Apr 15. pii: S2589-5559(26)00118-7. [Epub ahead of print] 101847

Loss of Hepatocyte PI3Kα Reduces Hepatocellular Carcinoma and Hepatocyte Proliferation in Association with Altered Lipid Metabolism.

Barbara Becattini, Claudia Sardi, Bart Edelbroek, Amit Chand Gupta, Toshima Parris, Khalil Helou, Giovanni Solinas.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a disease with an increasing incidence and a high mortality rate. Thus, targeted therapies for HCC are urgently needed. PI3K-AKT-mTORC1 signaling is frequently induced in solid tumors and is associated with tumor progression and with the most aggressive type of HCC. However, complete inhibition of all PI3K isoforms is unlikely to achieve a favorable therapeutic index for HCC treatment due to on-target side effects. In this manuscript, we investigate the role of hepatocyte PI3Kα activity in HCC.
METHODS: Here, we investigate the role of hepatocyte PI3Kα in HCC using conditional knockout mice in the N-nitrosodiethylamine (DEN) plus high fat diet (HFD) model of HCC.
RESULTS: Mice lacking PI3Kα in the hepatocyte are protected from DEN-induced HCC (n=8-17, p<0.005). We found that PI3Kα in the hepatocyte is dispensable for AKT phosphorylation in HCC and normal liver (n=4). PI3Kα is also dispensable for AKT phosphorylation in hepatocytes during compensatory proliferation following acute administration of the hepatocarcinogen (n=3-4). We also found that AKT phosphorylation induced by hepatocyte growth factor (HGF) and epidermal growth factor (EGF) is mediated by redundant PI3Kα and PI3Kβ activities (n=3-4). Nonetheless, mice lacking hepatocyte PI3Kα showed reduced HCC proliferation and reduced hepatocyte proliferation acutely induced by diethylnitrosamine (DEN) and induced by HGF and EGF (n=3, p<0.05). This phenotype was associated with a gene expression signature indicating altered lipid metabolism and reduced formation of lipid droplets (n=7).
CONCLUSIONS: Together, these results indicate that PI3Kα is a promising target for the treatment of HCC.
IMPACT AND IMPLICATIONS: Class-1 phosphoinositide 3-kinases (PI3Ks) are frequently activated in tumors, but complete inhibition of PI3K signaling is associated with liver damage and hepatocellular carcinoma (HCC). We now show that selective ablation of the PI3Kα isoform in the hepatocyte drastically reduces HCC development in mice injected with a hepatocarcinogen. This phenotype was associated with reduced hepatocyte proliferation and a gene expression signature indicative of altered lipid metabolism and reduced lipid droplet formation. Altogether, our results indicate that PI3Kα is a promising drug target for the treatment of HCC.

DOI: https://doi.org/10.1016/j.jhepr.2026.101847
PLoS Comput Biol. 2026 Apr;22(4): e1014067

Unveiling gene perturbation effects through gene regulatory networks inference from single-cell transcriptomic data.

Clelia Corridori, Merrit Romeike, Giorgio Nicoletti, Christa Buecker, Samir Suweis, Sandro Azaele, Graziano Martello.

Physiological and pathological processes are governed by networks of genes called gene regulatory networks (GRNs). By reconstructing GRNs, we can accurately model how cells behave in their natural state and predict how genetic changes will affect them. Transcriptomic data of single cells are now available for a wide range of cellular processes in multiple species. Thus, a method building predictive GRNs from single-cell RNA sequencing (scRNA-seq) data, without any additional prior knowledge, could have a great impact on our understanding of biological processes and the genes playing a key role in them. To this aim, we developed IGNITE (Inference of Gene Networks using Inverse kinetic Theory and Experiments), an unsupervised machine learning framework designed to infer directed, weighted, and signed GRNs directly from unperturbed single-cell RNA sequencing data. IGNITE uses the GRNs to generate gene expression data upon single and multiple genetic perturbations. IGNITE is based on the inverse problem for a kinetic Ising model, a model from statistical physics that has been successfully applied to biological networks. We tested IGNITE on two complementary systems of pluripotent stem cells (PSCs): murine PSCs transitioning from the naïve to formative states, and human PSCs differentiating toward definitive endoderm. These datasets differ in species, developmental trajectory, and single-cell technology (10X vs. Fluidigm C1), providing a stringent test of generalizability. Using only unperturbed scRNA-seq data, IGNITE simulated single and multiple gene knockouts (KOs) and produced predictions consistent with independent experimental observations. In mouse PSCs, IGNITE generated wild-type data highly correlated with experiments and accurately predicted the effects of Rbpj, Etv5, and triple KOs, while in human PSCs it correctly predicted differentiation-promoting and differentiation-blocking perturbations, in agreement with published studies. These results demonstrate that IGNITE robustly captures gene interaction logic across species and technologies, enabling robust in silico perturbation analyses directly from scRNA-seq data.

DOI: https://doi.org/10.1371/journal.pcbi.1014067
Nat Commun. 2026 Apr 16.

Clonal biases dictate availability of colonic cancer driver mutations for transformation.

Nefeli Skoufou-Papoutsaki, Richard Kemp, Sam Adler, Kate Marks, Anne-Claire Girard, Shenay Mehmed, Filipe C Lourenço, Elisa B Moutin, Rogier Ten Hoopen, Edward Morrissey, Douglas J Winton, David S Tourigny.

Aged normal tissues harbour cancer mutations predisposing to transformation. However, how different pro-oncogenic events in the human colon compare in frequency, behaviour and subsequent transformation risk remains unclear. Here, we analyse mutation hotspot regions in five colorectal cancer genes (APC, KRAS, TP53, FBXW7 and CTNNB1) using targeted sequencing of 76,800 normal colonic glands from 56 patients. We show that cancer-driving mutations are present in all genes in histologically normal tissue. Reconstruction of clone dynamics reveals that FBXW7 R465C mutations preferentially become fixed within the tissue, whereas KRAS G12 mutations strongly promote expansion. Modelling mutation order indicates that early loss of both APC copies increasingly favours an APC-first pathway with age, while KRAS activation is equally likely to initiate events in younger individuals. Spatial transcriptomics highlights phenotypic heterogeneity among KRAS mutant clones, with mixed lineage presentation observed only in a subset, a state linked to elevated transformation risk in other organs.

DOI: https://doi.org/10.1038/s41467-026-71944-5
Front Cardiovasc Med. 2026 ;13 1760326

Identification of pathological CD133+ endothelial cells in venous malformations.

Carrie J Shawber, Averill Clapp, Noa Shapiro-Franklin, Shirley Yang, Mason G Harvill, Emma Iaconetti, Michael J Schonning, Andrew I Zeiler, Meghan Perez, Seung Koh, Anna Alkelai, June K Wu.

   Introduction: Venous malformations (VMs) are congenital malformations of the venous system. Histologically, they are composed of dilated vascular channels. Prior studies have demonstrated that CD31 + endothelial cells (ECs) in VMs have pathogenic variants. Recent studies by our group found that the EC progenitor marker, CD133+, was expressed on VM endothelium in patient tissues. We hypothesized that a CD133+ VM endothelial cells contributes to VM pathobiology.
Methods: VM cells were isolated from resected venous malformation tissues or fluid using CD133 as a marker. Isolated VM populations were characterized by quantative RT-PCR, fluorescence-activated cell sorting (FACS) and immunofluorescence staining (IF) for the expression of progenitor and mature EC genes/proteins. Cells underwent whole exome sequencing (WES) to probe for genetic variants. AKT and ERK activation status was assessed by Western blot and IF, and cell proliferation determined. Isolated CD133+ cells were xenografted in mice and their ability to recapitulate VM phenotype was assessed by histological analysis, IF and colormetric staining.
Results: CD133+ cells isolated from VMs expressed progenitor and mature EC genes and proteins, and we termed them CD133+ VM endothelial cells (CD133+ VMECs). WES revealed CD133+ VMECs had pathogenic variants and variants of uncertain significance in genes reported in VMs, PIK3CA and TEK. CD133+ VMECs had increase proliferation and a subset had increase nuclear phospho-AKT. When implanted into a xenograft model, CD133+ VMECs with PIK3CA and TEK variants recapitulated clinical VM phenotypes.
Conclusion: We have identified a novel cell type in VMs, CD133+ VMECs that express EC progenitor proteins, demonstrating incomplete or misdirected differentiation down the EC lineage and are capable of recapitulate the phenotype in a mouse model.

Keywords:  endothelial cells; progenitor; venous malformations; whole exome sequencing; xenograft

DOI:  https://doi.org/10.3389/fcvm.2026.1760326
PNAS Nexus. 2026 Apr;5(4): pgag089

Aging changes cell mechanics and dynamics associated with cytoplasmic crowding.

Lani D Lee, Yuechuan Lin, Krishna C Penumatsa, Peter T C So, Ming Guo.

  Aging induces physical changes in organisms, many of which are at the cellular level, but the mechanisms underlying these changes are poorly understood. While the cytoplasm provides a crucial physical environment to host essential cellular processes, how its properties change in aging remains largely unknown. Here, using cells from well-established aging mice models, we first investigate the morphological and dynamic changes of aging cells and how they relate to the physical state of the cytoplasm. We find that aged cells spread larger and rounder and migrate slower than young cells. Using particle fluctuation, optical tweezers, and force spectrum microscopy, we demonstrate that aging increases cytoplasmic stiffness and reduces intracellular movement, even while active intracellular forces increase. In addition, using tomographic phase microscopy, we observe a higher refractive index in aged cells which indicates a denser cytoplasm, hinting that aging causes a more crowded cell interior. This crowding behavior underlines the increased cytoplasmic stiffness and the decreased intracellular movement, thereby influencing the altered cell behavior. Our results imply a crucial physical mechanism behind cellular-level changes due to aging. Though mechanisms behind these observations remain unclear, this understanding of cells' physical nature may support fundamental biological functions explored in aging research.

Keywords:  aging; cell mechanics; cytoplasm; intracellular crowding

DOI:  https://doi.org/10.1093/pnasnexus/pgag089
Mol Cancer Ther. 2026 Mar 15.

Targeting the chromatin modifying enzyme, KDM5C, enhances AKT inhibition response in ER+ breast cancer.

Valentina Cutano, Shanade Dunn, Sungmi Park-Chouinard, Eleanor M Wigmore, Qing Wu, Lambert Montava Garriga, Lorna Hopcroft, David Esopi, Michele Chirichella, Siyu Liu, Cath Eberlein, Ming Tang, Hyung Joo Lee, Wenhao Zhang, Megan Callahan, Barrett R B Nuttall, Daniel Barrell, Toby Gurran, Jennifer Hillis, Adam Spruce, Ramy Elgendy, Jenna Bradley, Chang Kim, Sara Talbot, Lingling Dai, Laura H Rosenberg, Susana Ros, Huayang Liu, Neeraj Aryal, Jerome T Mettetal, Ho Man Chan, Ultan McDermott, Functional Genomics Centre, Simon T Barry.

The AKT inhibitor capivasertib has demonstrated clinical benefit in combination with the selective ER degrader fulvestrant in PIK3CA, PTEN and AKT-1 altered estrogen receptor positive breast cancer (ER+ BC). A genome-wide CRISPR screen was performed in PI3K-AKT pathway altered ER+ BC cells exploring modifiers of response to capivasertib which identified different resistance and sensitivity drivers. Loss of chromatin regulators including KDM5C and KAT6A increased sensitivity to capivasertib. Genetic knockout or pharmacological inhibition of KDM5C strongly enhanced the anti-proliferative effects of capivasertib monotherapy, as well as in combination with fulvestrant in treatment naïve and endocrine therapy or capivasertib resistant ER+ BC cell lines. RNA-seq and epigenetic profiling revealed that combining capivasertib with KDM5C KO had a modest effect on gene transcription, with some effect on cell cycle related genes and ER signalling. In contrast, combining capivasertib with fulvestrant enhanced the effects of fulvestrant on transcriptional output and promoter occupancy. Rather than influencing gene expression, loss of KDM5C combined with capivasertib increased cell stress, DNA damage, cell cycle arrest and cell death. Collectively the data suggests that chromatin regulators may have different functions following capivasertib treatment, with inhibition having potential to enhance sensitivity to capivasertib in PIK3CA, PTEN and AKT-1 altered ER+ BC cells.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1006
Nutrients. 2026 Mar 29. pii: 1095. [Epub ahead of print]18(7):

Endothelial Cells as Active Lipid Gatekeepers: Vascular Control of Lipid Handling and Metabolic Homeostasis.

Takeshi Kanda, Hidonori Urai.

  Endothelial cells have emerged as critical peripheral nutrient sensors that actively regulate systemic lipid metabolism rather than serving as passive conduits. Endothelial peroxisome proliferator-activated receptor γ maintains redox balance, supports nitric oxide-dependent perfusion, and preserves insulin sensitivity during high-fat feeding, while ghrelin signaling through endothelial GHS-R promotes triglyceride clearance and lipid uptake into white adipose tissue through an endothelial peroxisome proliferator-activated receptor γ-dependent program. These pathways reveal that the endothelium integrates hormonal and metabolic cues to tune lipid trafficking, vectorial fatty acid delivery, and depot-specific energy storage. The concept that the endothelial phenotype, rather than circulating lipid levels alone, determines organ-level lipid exposure reframes endothelial lipid sensing as a key regulator of whole-body metabolic homeostasis. Understanding how endocrine and transcriptional pathways shape endothelial lipid handling may reveal new therapeutic targets for the treatment of obesity, dyslipidemia, and related metabolic diseases.

Keywords:  CD36; GHS-R; GPIHBP1; adipose tissue; endothelium; heart; lipoprotein lipase; liver sinusoidal endothelium; peroxisome proliferator-activated receptor γ; skeletal muscle

DOI:  https://doi.org/10.3390/nu18071095