bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–09–20
seventeen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Precision Medicine for Somatic Mutation-Driven Vascular Anomalies.
  2. Akt signaling regulates the activities of lymphatic malformation endothelial cells through PKM2 nuclear translocation.
  3. scBaseCount: An AI agent-curated, standardized, auto-updated single-cell data repository.
  4. Tahoe-100M: Mapping drug-induced molecular phenotypes at single-cell resolution.
  5. Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.
  6. Quantitative imaging of dynamic processes in intestinal organoids.
  7. Advances in the Targeted Therapy for PIK3CA-Related Overgrowth Spectrum (PROS): From Molecular Mechanisms to Clinical Translation.
  8. The clinical and phenotypic spectrum of PTEN hamartoma tumor syndrome: a retrospective cohort study.
  9. Large serine recombinase-mediated gene insertion for high-throughput screens: advantages, design principles, and applications.
  10. The power of theory in the life sciences.
  11. FoxO transcription factors coordinate the urea cycle and gluconeogenesis by controlling Ass1.
  12. Managing capivasertib-induced hyperglycemia: a report of 3 cases.
  13. Cell Painting in activated cells illuminates phenotypic dark space and drug mechanisms of action.
  14. Targeted genomic integration and rearrangement using prime assembly.
  15. BET Protein Degrader ZBC260 Induces Tumor Vascular Reprogramming Through Endothelial Cell Remodeling.
  16. Cancer treatment alters mutant selection in normal esophagus.
  17. Structure and function of TM6SF1 reveals role in mTORC1 signaling.
  1. Br J Dermatol. 2026 Sep 17. pii: ljag409. [Epub ahead of print]
    Precision Medicine for Somatic Mutation-Driven Vascular Anomalies.
    Yulang Xu, Jiangyuan Zhou, Yuru Lan, Yi Ji.
      Vascular anomalies, including proliferative vascular tumours and structural malformations, are largely driven by postzygotic somatic mutations that constitutively activate key signalling pathways, mainly the PI3K/AKT/mTOR and RAS/MAPK pathways. This molecular understanding has shifted clinical management from empiric interventions towards precision medicine. In this review, the interactions between somatic mosaicism, germline predispositions (e.g., PTEN hamartoma tumour syndrome), and microenvironmental risk factors in the context of lesional progression are described. We synthesized data on genotype‒phenotype correlations-such as PIK3CA mutations in lymphatic and venous malformations, KRAS/MAP2K1 mutations in arteriovenous malformations, and cerebral cavernous malformation (CCM) complex dysfunctions in cerebral cavernous anomalies-while fundamentally differentiating the mechanistic dependencies of true malformations from those of proliferative tumours. Targeted therapies, including mTOR, PI3Kα, and MEK inhibitors, have exhibited significant clinical efficacy in the treatment of pathway-specific anomalies. Despite these advances, therapeutic resistance and drug dependency persist. Future directions include the development of integrated diagnostic frameworks combining tissue biopsies with longitudinal cell-free DNA (cfDNA) monitoring, optimizing dual-pathway combination strategies, and advancing cellular models to reshape the management of vascular anomalies.
    DOI:  https://doi.org/10.1093/bjd/ljag409
  2. Biochim Biophys Acta Mol Basis Dis. 2026 Sep 12. pii: S0925-4439(26)00328-5. [Epub ahead of print]1873(1): 168462
    Akt signaling regulates the activities of lymphatic malformation endothelial cells through PKM2 nuclear translocation.
    Peipei Wang, Suyang Chen, Rong Wang, Guoyong Tong, Shaodong Yang, Wenqun Zhong, Yu Cai.
      Lymphatic malformation (LM) is a developmental lymphatic anomaly characterized by abnormally activating lymphatic endothelial cells (LECs) and lymphangiogenesis. Recent studies have shown that glycolysis can promote LM progression and pyruvate kinase M2 isoform (PKM2) is highly expressed in LM, whereas the mechanism involved remains unknown. In this study, we explored the mechanism for nuclear translocation of PKM2 in LECs isolated from LM (LM-LECs). Metabolic flux analyses, cell migration, cell invasion, and tube formation assays were performed to investigate the glycolysis level and activities of LM-LECs. A higher level of glycolysis was present in LM-LECs than that in human dermal lymphatic endothelial cells (HDLECs), which was associated with PKM2 expression, especially nuclear PKM2. Furthermore, inhibiting the nuclear translocation of PKM2 obviously restrained the activity of LM-LECs. Mechanistically, the data from RNA-seq and western blot showed that the level of nuclear PKM2 was regulated by PI3K-Akt pathway in LM-LECs. In sum, our results demonstrate that the PI3K-Akt signaling pathway is activated in LM-LECs, promoting the nuclear translocation of PKM2 and subsequently upregulating glycolysis level in LM-LECs. Conversely, inhibition of the dimeric PKM2 significantly suppresses LM-LEC activity.
    Keywords:  Akt; Dimeric PKM2; Glycolysis; Lymphatic endothelial cells; Lymphatic malformation
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168462
  3. Cell. 2026 Sep 17. pii: S0092-8674(26)00998-0. [Epub ahead of print]189(19): 5932-5944.e6
    scBaseCount: An AI agent-curated, standardized, auto-updated single-cell data repository.
    Nicholas D Youngblut, Christopher Carpenter, Arshia Nayebnazar, Abhinav Adduri, Rohan Shah, Chiara Ricci-Tam, Jaanak Prashar, Rajesh Ilango, Noam Teyssier, Silvana Konermann, Patrick D Hsu, Alexander Dobin, Dave P Burke, Hani Goodarzi, Yusuf H Roohani.
      Single-cell RNA sequencing has transformed cell biology by enabling precise transcriptomic measurements of individual cells. The Sequence Read Archive (SRA) is the largest public repository of sequencing reads, yet much of it remains underutilized due to unstandardized metadata. Here, we introduce scBaseCount, a database that leverages an AI agent to automate discovery and metadata extraction and standardize data processing. Built by mining all 10x Genomics datasets, scBaseCount is the largest public repository of single-cell gene expression data, comprising over 502 million cells across 27 organisms and 75 tissues. It offers an unbiased view of the data landscape within the SRA and enables the training of more performant computational models through access to broader phenotypic diversity. Uniform processing enables measurement of both intronic and exonic reads and non-coding gene expression and improves alignment across experiments. Moreover, scBaseCount provides a blueprint for how AI can be leveraged to autonomously curate biological data repositories.
    Keywords:  agents; artificial intelligence; cell biology; cross-species; data curation; data repository; gene expression; single-cell RNA-seq; transcriptomics
    DOI:  https://doi.org/10.1016/j.cell.2026.08.025
  4. Cell. 2026 Sep 17. pii: S0092-8674(26)01008-1. [Epub ahead of print]189(19): 5945-5961.e8
    Tahoe-100M: Mapping drug-induced molecular phenotypes at single-cell resolution.
    Jesse Zhang, Airol A Ubas, Valentine Svensson, Nicole Thomas, Vishvak Subramanyam, Christopher Carpenter, Aidan Winters, Richard de Borja, Noam Teyssier, Neha Thakar, Umair Khan, Pooja V Akella, Harper J Green, John D Thompson, Vuong Tran, Joseph Pangallo, Efthymia Papalexi, Ajay Sapre, Hoai Nguyen, Oliver Sanderson, Maria Nigos, Olivia Kaplan, Sarah Schroeder, Bryan Hariadi, Simone Marrujo, Crina Curca, Alec Salvino, Guillermo Gallareta Olivares, Ryan Koehler, Alexander Rosenberg, Charles Roco, Chiara Ricci-Tam, Matthew G Jones, Alexander Dobin, Brian S Plosky, Danielle E Lyons, Daniele Merico, Nima Alidoust, Hani Goodarzi, Johnny Yu.
      We present Tahoe-100M, a giga-scale single-cell perturbation atlas comprising 100 million transcriptomes from 50 diverse cancer cell lines treated with 1,100 drug-dose conditions. This parallel profiling of thousands of perturbations at single-cell resolution with minimal batch effects is enabled by the Mosaic platform, which multiplexes genetically distinct cell models into balanced "cell villages." Beyond cataloging transcriptomic shifts, Tahoe-100M systematically quantifies cellular phenotypes, including proliferation, cytotoxicity, lineage-specific vulnerabilities, and cell-cycle changes. It captures population-level transcriptomic heterogeneity, characterizing whether drug responses drive cells toward divergent fates or convergent states. Pathway-based signatures define drug-induced expression programs, classify mechanisms of action, reveal off-target activities, and expose adaptive stress responses associated with resistance. By unifying cellular and molecular readouts, this broadly applicable perturbation atlas advances our ability to model gene regulation, drug response, and network dynamics. Its public release enables the training of AI frameworks to advance predictive models of cell behavior.
    DOI:  https://doi.org/10.1016/j.cell.2026.08.035
  5. Nat Commun. 2026 09 16. pii: 9877. [Epub ahead of print]17(1):
    Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.
    Nádia Da Silva Fernandes, Fridolin Kielisch, Amitkumar Fulzele, Sivarajan Karunanithi, Justus F Gräf, Jia-Xuan Chen, Christian Behl, Helle D Ulrich, Petra Beli.
      Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated manner, characterized by widespread protein depletion on chromatin. Moreover, components of the cytoplasmic translation machinery are depleted, while mitochondrial proteins display increased insolubility. Autophagic and proteasome activity is compromised in senescent cells along with remodeling of ubiquitin linkages and depletion of ubiquitin E3 ligases. Comparison of the senescent proteome with different pathophysiological cellular states reveals a distinctive senescent signature shaped by changes in the proteostasis network. Collectively, we provide a resource for the exploration of temporally resolved changes in the senescent proteome.
    DOI:  https://doi.org/10.1038/s41467-026-77686-8
  6. Nat Protoc. 2026 Sep 15.
    Quantitative imaging of dynamic processes in intestinal organoids.
    Willem Kasper Spoelstra, Xuan Zheng, Rutger N U Kok, Guizela Huelsz-Prince, Max Betjes, Pascal Ender, Yvonne Goos, Kim A Kuentzelmann, Heidi E Klumpe, Daniel Krueger, Daisong Wang, Hans Clevers, Sander J Tans, Jeroen S van Zon.
      Organoids are powerful models for studying tissue dynamics across multiple cellular generations and offer key insights into organ homeostasis, cellular differentiation and disease. Live imaging of organoids is an essential tool for understanding dynamic processes on the cell level, while still in the tissue context. It allows for simultaneous quantification of gene expression and reconstruction of lineage trees, while tracking cells over space and time. Here, we present protocols for long-term imaging and quantitative analysis of intestinal organoids. Our workflow consists of sample preparation, experimental manipulations (such as drug treatments, laser ablations and fluorescence recovery after photobleaching), long-term live imaging (120 h), in situ fixation and permeabilization, multiplexed antibody staining and single-cell tracking with lineage reconstruction. The workflow is broadly applicable to studying dynamic cellular processes in both 2D and 3D organoids, at timescales from minutes to days. We outline strategies for optimizing organoid health, imaging conditions and experimental interventions to ensure efficient downstream analysis. In addition, we describe how this workflow enables real-time quantification of gene expression using fluorescent reporters and inferring cell type changes by combining multiplexed antibody staining with cell-tracking data. The skills required for following these protocols are organoid culturing and standard live-cell confocal microscopy, and the full experimental protocol takes ~2 weeks. Together, these protocols provide a comprehensive approach for studying cellular behavior, lineage trees, expression dynamics and cell-cell interactions in organoids.
    DOI:  https://doi.org/10.1038/s41596-026-01432-z
  7. Pediatr Blood Cancer. 2026 Sep 16. e70697
    Advances in the Targeted Therapy for PIK3CA-Related Overgrowth Spectrum (PROS): From Molecular Mechanisms to Clinical Translation.
    Zhu Zhu, Si-Ming Yuan.
      The PIK3CA-related overgrowth spectrum (PROS) encompasses a group of rare, somatic disorders caused by somatic activating mutations in PIK3CA, resulting in a dysregulated PI3K/AKT/mTOR pathway and consequent segmental tissue overgrowth and vascular malformations affecting multiple tissue types. This review synthesizes advances in targeted therapy for PROS, focusing on molecular rationale, clinical evidence, limitations, and future perspectives of targeting the PI3K/AKT/mTOR pathway. Overall, the selective PI3Kα inhibitor alpelisib has shown reductions in lesion burden and improvements in functional outcomes, with a generally manageable safety profile. Other agents, including taselisib and miransertib, have shown limited clinical benefits, and their further development has been constrained by safety concerns and insufficient efficacy. Although mTOR inhibitors, such as sirolimus, have shown partial efficacy in symptom control, durable responses remain uncommon, and recurrence after treatment discontinuation has been observed. Long-term safety, particularly in pediatric populations, remains to be fully established. In conclusion, targeted therapies, particularly alpelisib, represent a significant advancement in the management of PROS, although optimization of patient selection, long-term risk assessment, and strategies to minimize recurrence remain important unmet needs.
    Keywords:  PI3K/AKT/mTOR pathway; PIK3CA‐related overgrowth spectrum; targeted therapy; vascular malformation
    DOI:  https://doi.org/10.1002/1545-5017.70697
  8. Fam Cancer. 2026 Sep 17. pii: 88. [Epub ahead of print]25(4):
    The clinical and phenotypic spectrum of PTEN hamartoma tumor syndrome: a retrospective cohort study.
    Einat Ritter, Aasem Abu Shtaya, Revital Kariv, Sari Lieberman, Elizabeth Half, Maria Postnikov, Guy Rosner, Hana Strul, Nathan Gluck, Lior Katz, Ephrat Levy-Lahad, Dalit May, Ido Laish, Yael Goldberg, Elez Vainer, Zohar Levi, Maya Aharoni Golan.
      PTEN Hamartoma Tumor Syndrome (PHTS) is a rare condition characterized by a complex phenotype including gastrointestinal hamartomas and increased lifetime malignancy risk. To characterize the clinical phenotype, genetic landscape, and spectrum of malignancies within a large cohort of adult PHTS carriers. A retrospective cohort study of adult patients (≥ 18 years) followed at specialized high-risk clinics who met PHTS diagnostic criteria based on either: (1) identification of a germline PTEN pathogenic/likely pathogenic variant, or (2) fulfillment of clinical criteria according to National Comprehensive Cancer Network (NCCN) guidelines. A total of 62 individuals were included (62.9% male; median age at inclusion 39.5, IQR, 28-52). All fulfilled diagnostic criteria for PHTS. PTEN pathogenic or likely pathogenic variant were identified in 50 individuals (80.6%). Colonic polyps were present in 40 patients. Malignancies were reported in 61% (n = 38), most frequently breast (n=13) and thyroid (n=7). Three individuals (4.8%) had rare soft tissue tumors: one with a desmoid tumor at age 18, one with concurrent axillary osteosarcoma and bilateral chest liposarcoma, and one with a skull-base sarcoma. Macrocephaly was observed in 33.8% (n = 21), and developmental delay, including autism spectrum disorder, in 8 patients (12.9%). One case of PTEN mosaicism was identified through tumor sequencing after negative blood genetic testing. Five individuals (8%) were treated with Sirolimus. This large cohort highlights the broad clinical spectrum and substantial cancer burden in PHTS, including rare soft tissue tumors. Constitutional mosaicism should be considered when clinical suspicion persists despite negative germline testing.
    Keywords:  Cowden -syndrome, soft tissue malignancy; Mosaicism; PTEN hamartoma tumor syndrome (PHTS)
    DOI:  https://doi.org/10.1007/s10689-026-00604-w
  9. Nucleic Acids Res. 2026 Sep 07. pii: gkag907. [Epub ahead of print]54(17):
    Large serine recombinase-mediated gene insertion for high-throughput screens: advantages, design principles, and applications.
    Andrea Martella, Kenneth A Matreyek, David I Fisher.
      High-throughput functional assays, such as multiplexed assays of variant effect (MAVE), increasingly demand stable, precise integration of large DNA libraries into mammalian genomes. While CRISPR-based technologies excel at localized, small-scale edits, they are constrained by payload size limits, heterogeneous editing outcomes, and, depending on the specific modality and repair pathway utilized, potential variability in junction fidelity during multikilobase insertions. In this review, we highlight large serine recombinases (LSRs) as highly efficient, single-enzyme alternatives for unidirectional, site-specific integration of large payloads with deterministic junctions. We survey targeted genomic integration strategies and detail best practices for implementing recombinase-based landing pad architectures. By enforcing single-copy, orientation-fixed integration at defined loci, landing pads decouple variant delivery from local chromatin effects to ensure the uniform, isogenic expression required for quantitative genotype-phenotype mapping. We further outline scalable applications of LSR-mediated integration across pooled and arrayed MAVE, CRISPR screens, and precise gene expression tuning. Finally, we assess current technological bottlenecks, particularly large donor delivery and the requisite pre-installation of canonical att recognition sites, while exploring emerging innovations in virus-like particle delivery, one-step CRISPR-recombinase systems, and computationally engineered programmable recombinases that promise to bypass these limitations and broaden mammalian genome engineering.
    DOI:  https://doi.org/10.1093/nar/gkag907
  10. Elife. 2026 Sep 18. pii: e112987. [Epub ahead of print]15
    The power of theory in the life sciences.
    Jacob L Fine, Finn Creeggan, Joshua Gertsvolf, Purav Gupta, Adam M R Groh.
      The rapid growth of high-throughput biology and genomics over the past two decades has helped catalogue many different aspects of gene function in diverse cell types and conditions. More recently, advances in artificial intelligence and deep learning have shown tremendous promise in making accurate predictions of functional genomics measurements. These advances make it tempting to equate experimental cataloguing and accurate prediction with the growth of our theoretical understanding of biological processes - an equivalence we believe is ultimately misleading.
    Keywords:  cell biology; computational biology; explanatory unification; history of biology; machine learning; none; philosophy of science; scientific practice; single-cell genomics; systems biology; theory
    DOI:  https://doi.org/10.7554/eLife.112987
  11. iScience. 2026 Sep 18. 29(9): 117399
    FoxO transcription factors coordinate the urea cycle and gluconeogenesis by controlling Ass1.
    Samia Karkoutly, Yoshinori Takeuchi, Zahra Mehrazad Saber, Duhan Tao, Tsolmon Mendsaikhan, Rika Saikawa, Yuichi Aita, Yuki Murayama, Akito Shikama, Yukari Masuda, Naoya Yahagi.
      Amino acid catabolism during fasting requires coordinated nitrogen disposal and glucose production, but the transcriptional logic linking the urea cycle to gluconeogenesis remains unclear. Forkhead box O (FoxO) transcription factors regulate fasting metabolism, and here we identify FoxOs as direct hepatic regulators of argininosuccinate synthase 1 (Ass1). Acute hepatic FoxO1/3a knockdown in fasted mice reduced Ass1 expression, lowered blood glucose, and altered urea-cycle amino acids, with decreased arginine and increased ornithine, even in Klf15-deficient livers. Ass1 silencing phenocopied these effects and impaired glucose production from pyruvate and lactate, whereas Ass1 overexpression restored glucose production in FoxO-inhibited hepatocytes. Mechanistically, we identified a functional FoxO-binding element within an upstream Ass1 enhancer and confirmed its fasting-inducible activity by reporter assays, electrophoretic mobility shift assays, in vivo imaging, and chromatin immunoprecipitation. These findings establish a KLF15-independent FoxO-Ass1 axis that coordinates ureagenesis with gluconeogenesis during fasting and supports hepatic metabolic adaptation to nutrient deprivation.
    Keywords:  amino acids; fasting; in vivo imaging; nutrigenomics; transcription factor; urea cycle
    DOI:  https://doi.org/10.1016/j.isci.2026.117399
  12. JCEM Case Rep. 2026 Oct;4(10): luag273
    Managing capivasertib-induced hyperglycemia: a report of 3 cases.
    Katherine Cuan, Sun Young Oh, Jovan Milosavljevic, Beatrice Y Wong.
      Phosphoinositide 3-kinase/protein kinase B (AKT) pathway inhibition is an important therapeutic strategy for hormone receptor positive and human epidermal growth factor receptor 2 negative advanced breast cancer. Capivasertib, an oral pan-AKT inhibitor, improves progression-free survival in combination with fulvestrant but is frequently associated with hyperglycemia. Despite this recognized adverse effect, consensus management guidelines are lacking. We describe 3 patients who developed capivasertib-associated hyperglycemia, 2 of whom had severe hyperglycemia with alpelisib therapy, a phosphoinositide 3-kinase inhibitor. Hyperglycemia developed early and was marked by postprandial excursions. All patients were treated with insulin-sensitizing therapies. Preemptive initiation or intensification of antihyperglycemic therapy before capivasertib exposure attenuated hyperglycemia severity. These cases highlight the insulin-resistant phenotype of AKT inhibitor-associated hyperglycemia and support early metabolic assessment, postprandial glucose monitoring, and preferential use of insulin-sensitizing therapies to minimize treatment interruption.
    Keywords:  AKT inhibitor; capivasertib; insulin resistance
    DOI:  https://doi.org/10.1210/jcemcr/luag273
  13. Nat Commun. 2026 Aug 14. pii: 9756. [Epub ahead of print]17(1):
    Cell Painting in activated cells illuminates phenotypic dark space and drug mechanisms of action.
    Matylda A Zietek, Akshar Lohith, Derfel Terciano, Beverley M Rabbitts, Aswad Khadilkar, John B MacMillan, R Scott Lokey.
      As drug and natural product libraries expand, assays for assessing mechanisms of action (MoA) are increasingly critical. Performing cytological profiling using the Cell Painting (CP) assay enables image-based profiling of cellular states upon treatment, yet many bioactive compounds remain uncharacterized due to undetectable cellular effects under standard conditions. To address this, we combine drug dosing with cell activation using the protein kinase C (PKC) agonist phorbol myristate acetate (PMA). Profiling A549 lung cancer cells treated with 8,387 compounds at two concentrations (1 and 10 µM) in both resting and PMA-activated states enables detection of phenotypic effects for up to 40% of all screened compounds, effectively illuminating more phenotypic 'dark space.' The combined cellular CP fingerprints from PMA-activated and resting cells reveal phenotypes for 565 compounds that are inactive under the resting condition alone, supporting its use in MoA studies. We introduce quality control measures for CP screens and demonstrate that integrating phenotypic signatures supports MoA discovery. Notably, 2-methoxycinnamaldehyde clusters with glucocorticoid receptor modulators and induces nuclear translocation, emphasizing the utility of this approach in identifying drug mechanisms and, therefore, aiding in improving therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-026-76252-6
  14. Nature. 2026 Sep 16.
    Targeted genomic integration and rearrangement using prime assembly.
    Sébastien Levesque, Nozomu Kawashima, Gue-Ho Hwang, Jing Zeng, Vasil Toskov, Timothy Barry, William Mannherz, Luke Homfeldt, Basheer Becerra, Vivien A C Schoonenberg, Luca Pinello, Suneet Agarwal, Daniel E Bauer.
      Although therapeutic genome editing holds great potential to remedy diverse inherited and acquired disorders, targeted installation of medium-to-large genomic modifications in therapeutically relevant cells remains challenging1. Here we develop prime assembly, an approach that permits DNA sequence assembly and integration in human cells leveraging CRISPR-targeted dual flap synthesis. This method enables RNA-programmable site-specific integration of single or double-stranded DNA fragments. Unlike homology-directed repair, prime assembly is similarly active in dividing and non-dividing cells. We applied prime assembly to perform targeted exon recoding, transgene integration and megabase-scale rearrangements, including at therapeutically relevant loci in primary human cells. Prime assembly expands the capabilities of genome engineering by enabling the targeted integration of medium to large-sized DNA sequences without relying on double-stranded DNA donors, nuclease-driven double-strand breaks or cell cycle progression.
    DOI:  https://doi.org/10.1038/s41586-026-11024-2
  15. Breast Cancer (Dove Med Press). 2026 ;18 626513
    BET Protein Degrader ZBC260 Induces Tumor Vascular Reprogramming Through Endothelial Cell Remodeling.
    Deeksha Sharma, Cody G Hager, Max S Wicha, Monika L Burness.
       Purpose: Endothelial cells regulate angiogenesis, matrix remodeling, and immune responses within the tumor microenvironment, yet endothelial cell heterogeneity across breast cancer subtypes and its regulation by bromodomain and extraterminal domain proteins remain unclear. This study profiled endothelial cells at single-cell resolution in two immunocompetent murine breast cancer models with distinct tumor immune microenvironments: PyMT_FVB/N and D2A1_BALB/c tumors.
    Methods: Mice were treated intravenously with the bromodomain and extraterminal domain degrader (ZBC260) at 10mg/kg 3 days/week until tumors reached humane endpoints and were harvested. Single-cell RNA sequencing was performed on vehicle and ZBC260 treated tumors (n=3 per condition), and endothelial cell populations were identified and analyzed using Seurat package in R.
    Results: Six transcriptionally distinct endothelial subpopulations were identified across both breast cancer models, with D2A1 tumors dominated by tip-like and proliferative endothelial cells with strong angiogenic and collagen-producing signatures. ZBC260 reprogrammed endothelial landscape by reducing proliferative, tip-like, and arterial endothelial cells while enriching venous and lymphatic endothelial cells. ZBC260 suppressed hypoxia, glycolysis, and mTORC1 signaling, downregulated angiogenesis and matrix associated pathways and was accompanied by reduced collagen signatures and increased leukocyte adhesion. Cell-cell communication analysis demonstrated that ZBC260 disrupted endothelial cells interactions with tumor and immune cells, by disrupting ligand-receptor communications and attenuating NOTCH, TGF-β, and VEGF signaling networks that sustain angiogenesis and immune suppression.
    Conclusion: Together, these findings highlight endothelial diversity across breast cancer models and identify ZBC260 as a regulator of tumor endothelial states. ZBC260 reprograms endothelial heterogeneity and remodels the tumor vascular landscape. The transcriptomic and cell-cell communication changes observed are consistent with the establishment of a more immune-permissive tumor microenvironment, supporting the potential of BET degradation as a strategy to complement immunotherapy and improve therapeutic responsiveness in breast cancer.
    Keywords:  ZBC260; endothelial cells; single cell RNA sequencing; tip-like ECs; tumor microenvironment
    DOI:  https://doi.org/10.2147/BCTT.S626513
  16. Nat Genet. 2026 Sep 11.
    Cancer treatment alters mutant selection in normal esophagus.
    Joanna C Fowler, Giuseppina Arbore, Roshan K Sood, Irina Abnizova, Luca Albarello, Oliver Pickering, Kasumi Murai, Ujjwal Banerjee, Salomé Brunon, Swee Hoe Ong, Andrea Cossu, Ugo Elmore, Francesco Puccetti, David Fernandez-Antoran, Giovanni Tonon, Paolo Dellabona, Riccardo Rosati, Samuel Luke Hill, Tim Underwood, Benjamin A Hall, David Shorthouse, Philip H Jones.
      Aging epithelial tissues, including the esophagus, are colonized by somatic mutant clones under strong competitive selection. The effect of cancer treatment on mutant selection in normal epithelium is unknown. We hypothesized that some mutant clones may be selectively expanded during treatment. To test this, we sequenced normal esophageal epithelium removed from 70 patients after therapy for esophageal cancer. Patients received either no treatment, combination chemotherapy (FLOT, ECX or EOX) or chemotherapy and radiation therapy (CROSS). Mutant TP53 and PPM1D clones were expanded in patients undergoing CROSS. In the group undergoing FLOT, there was increased selection for RAC1, NFE2L2 and MTOR mutations consistent with these mutants conferring 5-fluorouracil resilience in normal epithelium. Sequencing normal epithelia reveals treatment-specific selection of mutations and may identify genes implicated in cellular responses to therapy.
    DOI:  https://doi.org/10.1038/s41588-026-02738-0
  17. Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2622424123
    Structure and function of TM6SF1 reveals role in mTORC1 signaling.
    Sen Hong, Liangjie Jia, Rong Wang, Nadia Elghobashi-Meinhardt, Helen H Hobbs, Xiaochun Li.
      The transmembrane 6 superfamily (TM6SF) comprises two members: TM6SF1, a ubiquitously expressed lysosomal membrane protein of unknown function, and TM6SF2, an endoplasmic reticulum protein required for bulk lipidation of Apolipoprotein B-containing lipoproteins. Here, we used cryo-electron microscopy (cryo-EM) to determine the structure of human TM6SF1 at 2.9-Å resolution. TM6SF1 forms a polytopic homodimer, with each protomer comprising 10 transmembrane helices (TMs). TMs 1-6 form a pocket that accommodates a cholesterol molecule. Cell-based assays revealed that loss of TM6SF1 perturbs mTORC1 signaling, resulting in reduced phosphorylation of S6 kinase 1 and 4E-BP1 and constitutive activation of transcription factor EB (TFEB), and that cholesterol is required for these effects. Biochemical analyses support the model that TM6SF1 directly engages LAMTOR1, a component of Ragulator complex, in a cholesterol-dependent manner. Together, these findings identify TM6SF1 as a lysosomal cholesterol binding protein involved in regulating mTORC1 signaling.
    Keywords:  LAMTOR1; TM6SF1; cryo-EM; mTORC1; transcription factor EB
    DOI:  https://doi.org/10.1073/pnas.2622424123
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