bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–10–19
seventeen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Decoding class II PI3K signaling: From membrane identity to human disease.
  2. Neurodevelopmental and Neurologic Manifestations of PTEN Hamartoma Tumor Syndrome: Management Recommendations.
  3. HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.
  4. Image-Based Profiling in Live Cells Using Live Cell Painting.
  5. Sp1 mechanotransduction regulates breast cancer cell invasion in engineered viscoelastic extracellular matrices.
  6. Tuning insulin receptor signaling using de novo-designed agonists.
  7. ASPPs multimerize protein phosphatase 1.
  8. A human induced pluripotent stem cell toolbox for studying sex chromosome effects.
  9. Activation of a FOXO3-induced cell cycle arrest regulates ferroptosis.
  10. BIWT: a bioinformatics walkthrough for embedding spatial multiomics in agent-based models for virtual cells.
  11. Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.
  12. Phosphorylation of plectin by Akt3 promotes triple-negative breast cancer cell invasive migration.
  13. mTORC2-mediated cell-cell interactions promote BMP4-induced WNT activation and mesoderm differentiation.
  14. Combined MYC Activation and PTEN Loss Drives Molecular Features of Aggressive Preinvasive Lesions in Mouse Prostate.
  15. sc2DAT: workflow for targeting tumor subpopulations of single cells.
  16. A Roadmap for the Future of Systems Biology in Cancer Research.
  17. Embryonic stem cell-derived extracellular vesicles delay cellular senescence by inhibiting oxidative stress.
  1. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Oct 11. pii: S1388-1981(25)00101-5. [Epub ahead of print] 159693
    Decoding class II PI3K signaling: From membrane identity to human disease.
    Roberta Rubino, Gabriele Squillero, Lorenzo Prever, Emanuele Fantastico, Maria Chiara De Santis, Arezou Kahnamouei, Federico Gulluni, Emilio Hirsch.
      This review provides an integrated overview of the current understanding of class II PI3Ks, with particular attention to their structural and enzymatic properties, lipid substrate specificity, and emerging roles in membrane trafficking, cellular signaling, and disease. Class II phosphoinositide 3-kinases (PI3Ks) are lipid kinases that regulate membrane identity and intracellular signaling by generating phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2] at distinct subcellular compartments. Advances over the past decade have clarified the structural organization, regulatory principles, and lipid output of all the three mammalian isoforms (PI3K-C2α, PI3K-C2β, and PI3K-C2γ). These studies have revealed that class II PI3K function is highly context-dependent, governed by compartment-specific cues and the spatial restriction of lipid products. Dysregulation of class II PI3Ks has been implicated in diverse pathological conditions, including cancer, metabolic disorders, epilepsy, congenital myopathies, vascular dysfunction, and premature aging. These findings establish a framework for understanding how localized phosphoinositide synthesis contributes to cellular homeostasis and disease, and underscore the therapeutic potential of selectively targeting class II PI3K isoforms.
    Keywords:  Cell signaling; Class II PI3Ks; Phosphoinositides
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159693
  2. Neurol Genet. 2025 Oct;11(5): e200299
    Neurodevelopmental and Neurologic Manifestations of PTEN Hamartoma Tumor Syndrome: Management Recommendations.
    as the PTEN Hamartoma Tumor Syndrome Consensus Guidelines Working Group
       Background and Objectives: PTEN hamartoma tumor syndrome (PHTS) is an autosomal dominant cancer predisposition and overgrowth syndrome due to pathogenic germline variants in the PTEN gene. PHTS harbors a diverse range of clinical manifestations including an associated neurodevelopmental (ND) and neurologic phenotype, requiring a multidisciplinary approach to care. There are no clinical practice guidelines for the management of ND or neurologic comorbidities. The objective of these clinical guidelines was to use the latest knowledge to generate a resource for providers, researchers, and patients on the best practices in the practical management of neurologic and ND challenges in PHTS.
    Methods: The PHTS Consensus Guidelines Working Group was established, comprising a core group of seven experts in the diagnosis and management of PHTS, including genetics, neurology, neuropsychology, and neurodevelopment (including psychiatry and psychology). The Working Group held joint meetings with a Patient Advisory Group (PTEN Foundation), comprising patients with PHTS and their advocates. Informed by a comprehensive literature review, the Working Group met regularly between 2022 and 2024 to produce guideline statements, refined through iterative feedback. A modified Delphi approach was used with an independent extended panel of neurologists, neuropsychologists, and psychiatrists, to establish final consensus guidelines.
    Results: The first iteration of the clinical consensus recommendations for the management of ND and neurologic features in patients with PHTS was formed. Guidelines encompass ND challenges, mood disorders, ND screening, neuroimaging abnormalities, neurologic comorbidities, and tumors affecting the CNS.
    Discussion: While multiple efforts are ongoing to better characterize the natural history of PHTS, the clinical management of individuals with PHTS is complex and remains challenging because of variable expressivity and age-related specificities. As part of a comprehensive effort to develop consensus management guidelines, which cover all manifestations of PHTS, we present the first iteration of guidelines for the ND and neurologic manifestations of PHTS, aimed at improving care for affected individuals and families.
    DOI:  https://doi.org/10.1212/NXG.0000000000200299
  3. Cell Rep. 2025 Oct 09. pii: S2211-1247(25)01153-2. [Epub ahead of print]44(10): 116382
    HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.
    Takayuki Ikeda, Sungki Hong, Shota Yoshida, Swayam Prakash Srivastava, Abhiram Kunamneni, Yao Yao, Om Khuperkar, Venkatesha Basrur, Henry Kuang, Maureen Kachman, Abraham Raskind, Heidi Baum, Arya Joshi, Vinamra Swaroop, Aaron Thurman, Oliviamae Kopasz-Gemmen, Siddharth Kandukuri, F N U Pradeepa, Hideto Yonekura, Jiandie D Lin, Ken Inoki.
      The mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of cell growth, is activated by Rheb small GTPase. Our recent studies have demonstrated that polyubiquitinated Rheb enhances its interaction with mTORC1, resulting in the activation of mTORC1. Here, we demonstrate that the HECT, UBA, and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1), an E3 ubiquitin ligase, preferentially interacts with ubiquitinated Rheb and facilitates Rheb's binding to mTORC1 and its subsequent activation. The ablation of HUWE1 results in reduced ubiquitination of Rheb and decreased mTORC1 activity in cultured cells and mouse liver. HUWE1 is also necessary for Rheb to interact with carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase (CAD), a key enzyme in pyrimidine biosynthesis, and for CAD activation through the activation of the mTORC1-S6K1 pathway. Moreover, HUWE1 maintains CAD expression by increasing its transcript in cells and liver tissues. Therefore, HUWE1 acts as a key organizer of the ubiquitinated Rheb complex, playing a vital role in enhancing mTORC1 activity and pyrimidine synthesis by increasing both CAD activity and expression.
    Keywords:  CAD; CP: Cell biology; CP: Molecular biology; HUWE1; Rheb; mTOR; mTORC1; pyrimidine; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2025.116382
  4. Bio Protoc. 2025 Oct 05. 15(19): e5464
    Image-Based Profiling in Live Cells Using Live Cell Painting.
    Thaís Moraes-Lacerda, Mariana Rodrigues-Da-Silva, Shantanu Singh, Marcelo Bispo De Jesus.
      High-content analysis (HCA) is a powerful image-based approach for phenotypic profiling and drug discovery, enabling the extraction of multiparametric data from individual cells. Traditional HCA protocols often rely on fixed-cell imaging, with assays like cell painting widely adopted as standard. While these methods provide rich morphological information, the integration of live-cell imaging expands analytical capabilities by enabling the study of dynamic biological processes and real-time cellular responses. This protocol presents a simple, cost-effective, and scalable method for live-cell HCA using acridine orange (AO), a metachromatic fluorescent dye that highlights cellular organization by staining nucleic acids and acidic compartments. The assay provides visualization of distinct subcellular structures, including nuclei and cytoplasmic organelles, using a two-channel fluorescence readout. Compatible with high-throughput microscopy and computational analysis, the method supports diverse applications such as phenotypic screening, cytotoxicity assessment, and morphological profiling. By preserving cell viability and enabling dynamic, real-time measurements, this live-cell imaging approach complements existing fixed-cell assays and offers a versatile platform for uncovering complex cellular phenotypes. Key features • Builds upon Garcia-Fossa et al. [1], providing an accessible workflow for image-based profiling in live cells. • Enables phenotypic profiling and dose-response analysis of diverse perturbants, including small molecules, oligonucleotides, and nanoparticles. • Provides a live-cell framework to detect subtle, sublethal phenotypic changes, overcoming fixation assay limitations in toxicology and drug discovery. • Includes a streamlined analysis pipeline supporting efficient and reproducible interpretation of image-based data.
    Keywords:  Acridine orange staining; Fluorescence microscopy; High-content screening; Image-based phenotyping; Live-cell imaging
    DOI:  https://doi.org/10.21769/BioProtoc.5464
  5. Biomaterials. 2025 Oct 03. pii: S0142-9612(25)00674-X. [Epub ahead of print]327 123755
    Sp1 mechanotransduction regulates breast cancer cell invasion in engineered viscoelastic extracellular matrices.
    Abhishek Sharma, Rowan F Steger, Jen M Li, Samuel Y Fong, Neha Saxena, Jane A Baude, Kellie A Heom, Siddharth S Dey, Ryan S Stowers.
      Breast cancer progression involves extensive remodeling of the extracellular matrix (ECM), including increased stiffness, altered viscoelasticity (stress relaxation), and elevated collagen levels. While in vitro experiments have revealed a role for each of these factors in individually promoting malignant behavior, their combined effects remain unclear. Here, we engineered alginate-collagen hydrogels with independently tunable stiffness, stress relaxation, and collagen density to dissect how the complex ECM environment regulates cancer cell phenotype. We show that high stiffness, fast stress relaxation, and high collagen density led to changes in cell morphology, marked by decreased roundness, and promoted spheroid invasion in both breast cancer and non-transformed mammary epithelial cells. Single cell migration speed and displacement were greatest in matrices of high stiffness, low collagen density, and slow stress relaxation. RNA-seq and Cleavage Under Targets and Tagmentation (CUT&Tag)-seq revealed that high stiffness and fast stress relaxing groups were enriched for Sp1 target gene expression as well as increased Sp1 binding at genomic loci. Notably, analysis of publicly available claudin-low breast cancer data showed that high expression of the Sp1-regulated genes in fast stress relaxing groups was correlated with significantly reduced patient survival. Mechanistically, we found that phosphorylated Sp1 (T453) exhibited increased nuclear localization in matrices with high stiffness and fast stress relaxation. Furthermore, Sp1 phosphorylation was regulated by PI3K and ERK1/2 activity, as well as actomyosin contractility. Our tunable hydrogel platform reveals that multiple tumor-mimicking cues within complex viscoelastic microenvironments reinforce malignant traits, with Sp1 acting as a mechanoresponsive transcription factor that transduces these signals.
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123755
  6. Mol Cell. 2025 Oct 13. pii: S1097-2765(25)00780-4. [Epub ahead of print]
    Tuning insulin receptor signaling using de novo-designed agonists.
    Xinru Wang, Sarah Cardoso, Kai Cai, Preetham Venkatesh, Albert Hung, Michelle Ng, Catherine Hall, Brian Coventry, David S Lee, Rishabh Chowhan, Stacey Gerben, Jie Li, Weidong An, Mara Hon, Michael Gao, Ya-Cheng Liao, Domenico Accili, Eunhee Choi, Xiao-Chen Bai, David Baker.
      Insulin binding induces conformational changes in the insulin receptor (IR) that activate the intracellular kinase domain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways, regulating metabolism and proliferation. We reasoned that designed agonists inducing different IR conformational changes might induce different downstream responses. We used de novo protein design to generate binders for individual IR extracellular domains and fused them in different orientations with different conformational flexibility. We obtained a series of synthetic IR agonists that elicit a wide range of receptor autophosphorylation, MAPK activation, trafficking, and proliferation responses. We identified designs more potent than insulin, causing longer-lasting glucose lowering in vivo and retaining activity on disease-causing IR mutants, while largely avoiding the cancer cell proliferation induced by insulin. Our findings shed light on how changes in IR conformation and dynamics translate into downstream signaling, and with further development, our synthetic agonists could have therapeutic utility for metabolic and proliferative diseases.
    Keywords:  cancer; computational protein design; diabetes; insulin; insulin receptor; metabolism; receptor tyrosine kinase; severe insulin-resistance syndromes; signaling; trafficking
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.020
  7. PLoS Genet. 2025 Oct 16. 21(10): e1011731
    ASPPs multimerize protein phosphatase 1.
    Derek T Wei, Kayleigh N Morrison, Gwendolyn M Beacham, Erika Beyrent, Cyrus A Habas, Ying Zhang, Laurence Florens, Gunther Hollopeter.
      Protein Phosphatase 1 (PP1) activity is thought to be spatiotemporally defined by hundreds of different regulatory subunits, but their mechanisms of action are largely unknown. The Ankyrin repeat, SH3-domain, and Proline-rich region containing Proteins (ASPPs) bind and localize PP1 to cell-cell junctions. Here, we show ASPPs bind superstoichiometric amounts of PP1. Missense mutations in the ankyrin repeats of ASPPs, that were previously isolated from a forward genetic screen in Caenorhabditis elegans, reduce the stoichiometry of PP1 binding. Forcing PP1 oligomerization restores mutant ASPP function in vivo. We propose that ASPPs multimerize PP1 to establish a concentrated hub of phosphatase activity at cell-cell junctions.
    DOI:  https://doi.org/10.1371/journal.pgen.1011731
  8. Stem Cell Reports. 2025 Oct 16. pii: S2213-6711(25)00282-6. [Epub ahead of print] 102678
    A human induced pluripotent stem cell toolbox for studying sex chromosome effects.
    Ruta Meleckyte, Wazeer Varsally, Jasmin Zohren, Jerry Eriksson, Tania Incitti, Linda Starnes, Amy Pointon, Ryan Hicks, Benjamin E Powell, James M A Turner.
      Sex chromosomes shape male (XY)-female (XX) differences in development and disease. These differences can be modeled in vitro by comparing XY and XX human induced pluripotent stem cells (hiPSCs). However, in this system, inter-individual autosomal variation and unstable X-dosage compensation can confound identification of sex chromosomal effects. Here, we utilize sex chromosome loss in XXY fibroblasts to generate XX and XY hiPSCs that are autosomally isogenic and exhibit stable X-dosage compensation. We also create X-monosomic (XO) hiPSCs, to investigate X-Y dosage effects. Using these autosomally isogenic lines, we examine sex differences in pluripotent stem cell expression. Transcriptional differences between XX and XY hiPSCs are surprisingly modest. However, X-haploinsufficiency induces transcriptional deregulation predominantly affecting autosomes. This effect is mediated by Y-genes with broad housekeeping functions that have X-homologs escaping X inactivation. Our isogenic hiPSC lines provide a resource for exploring sex chromosome effects on development and disease in vitro.
    Keywords:  disease modeling; hiPSCs; human; iPSC model; iPSCs; induced pluripotent stem cells; sex differences; sexual dimorphism
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102678
  9. Cell Death Discov. 2025 Oct 16. 11(1): 465
    Activation of a FOXO3-induced cell cycle arrest regulates ferroptosis.
    Huanjie Huang, Matthias van Sligtenhorst, Alida M M Smits, Can Gulersonmez, Edwin Stigter, Tobias B Dansen, Boudewijn M T Burgering.
      FOXO transcription factors act downstream of PI3K signaling, and FOXO transcriptional activity is inhibited through nuclear exclusion by PKB/AKT-mediated phosphorylation. Many studies have shown FOXO to contribute to organismal homeostasis by mitigating (extra)cellular stress to prevent cell death (reviewed in [1]). Here we show that FOXO3 activation protects cells from ferroptosis, an iron-dependent form of non-apoptotic cell death. In untransformed hTERT-RPE-1 cells, FOXO3 activation reduces ferroptosis in a multilayered manner. First, FOXO3 mediates protection from ferroptosis in part through a p27-induced G1 cell cycle arrest. Second, FOXO3 activation reduces cellular H2O2 levels, thereby limiting substrate availability for the Fenton reaction, which fuels hydroxyl radical formation for lipid peroxidation. Third, FOXO3 activation lowers cellular iron content by reducing TFR1 expression, which, combined with the lowering of cellular H2O2 levels, likely further reduces the formation of hydroxyl radicals through the Fenton reaction. Finally, FOXO3 activation reduces expression of long-chain-fatty-acid-CoA ligase 4 (ACSL4) and Peroxisomal targeting signal 1 receptor (PEX5), proteins involved in lipid metabolism and protection against ferroptosis. Taken together, we show that FOXO3 activation results in protection from ferroptosis, adding to the repertoire of FOXO-controlled cell protection programs.
    DOI:  https://doi.org/10.1038/s41420-025-02760-x
  10. Bioinformatics. 2025 Oct 16. pii: btaf571. [Epub ahead of print]
    BIWT: a bioinformatics walkthrough for embedding spatial multiomics in agent-based models for virtual cells.
    Daniel R Bergman, Jeanette Johnson, Marwa Naji, Maxwell Booth, Heber Lima da Rocha, Atul Deshpande, Dimitrios N Sidiropoulos, Tamara Lopez-Vidal, Randy Heiland, Luciane T Kagohara, Robert A Anders, Lei Zheng, Elizabeth M Jaffee, Genevieve Stein-O'Brien, Paul Macklin, Elana J Fertig.
       SUMMARY: Whereas transcriptomic and spatial profiling offer static snapshots of tissue structure, mechanistic models use biological rules to predict how tissues evolve. We present the BioInformatics WalkThrough (BIWT) software to directly initialize spatial agent-based models (ABMs) from single-cell and spatial molecular data. We demonstrate how initialization strategies affect tumor-immune dynamics and spatial clustering, positioning BIWT as a software suite to generate data-driven virtual cells representing both experimental and clinical contexts.
    AVAILABILITY AND IMPLEMENTATION: The BIWT software is available at https://github.com/PhysiCell-Tools/PhysiCell-Studio. The sample dataset for running the BIWT is available at https://zenodo.org/records/16365625. The code and instructions for reproducing the use case example is available at https://github.com/drbergman/BIWT-Paper.
    SUPPLEMENTARY INFORMATION: The online supplementary link will be placed here when it is finalized.
    Keywords:  agent-based model; multiomics; predictive modeling; spatial multiomics; virtual cells
    DOI:  https://doi.org/10.1093/bioinformatics/btaf571
  11. Nat Commun. 2025 Oct 15. 16(1): 9143
    Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.
    Vahid Aslanzadeh, Gemma V Brierley, Rupa Kumar, Hasan Çubuk, Corinne Vigouroux, Kenneth A Matreyek, Grzegorz Kudla, Robert K Semple.
      The insulin receptor entrains tissue growth and metabolism to nutritional conditions. Complete loss of function in humans leads to extreme insulin resistance and infantile mortality, while loss of 80-90% function permits longevity of decades. Even low-level activation of severely compromised receptors, for example by anti-receptor monoclonal antibodies, thus offers the potential for decisive clinical benefit. A barrier to genetic diagnosis and translational research is the increasing identification of variants of uncertain significance in the INSR gene, encoding the insulin receptor. By coupling saturation mutagenesis to flow-based assays, we stratified approximately 14,000 INSR extracellular missense variants by cell surface expression, insulin binding, and insulin- or monoclonal antibody-stimulated signalling. Resulting function scores correlate strongly with clinical syndromes, offer insights into dynamics of insulin binding, and reveal novel potential gain-of-function variants. This INSR sequence-function map has biochemical, diagnostic and translational utility, aiding rapid identification of variants amenable to activation by non-canonical INSR agonists.
    DOI:  https://doi.org/10.1038/s41467-025-64178-4
  12. iScience. 2025 Oct 17. 28(10): 113552
    Phosphorylation of plectin by Akt3 promotes triple-negative breast cancer cell invasive migration.
    Shixue Zheng, Chloe Chan, John M Asara, Liang Zhang, Gerhard Wiche, Y Rebecca Chin.
      Triple-negative breast cancer (TNBC) lacks targeted therapeutics and is aggressive with a poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, frequently deregulated in cancers, plays crucial roles in tumorigenesis and cancer progression. However, the distinct functions of the three Akt isoforms (Akt1, Akt2, Akt3) in these processes are not well understood. Here, we focus on Akt3, the least-studied Akt isoform, which is overexpressed in 28% of TNBC cases and significantly promotes TNBC growth, stemness, and epithelial-mesenchymal transition. Through a genome-wide proteomic screen, we identified plectin, a member of the plakin family, as an Akt3 substrate in TNBC cells. The depletion of plectin potently inhibits TNBC cell migration and invadopodia formation, albeit with mild effects on cell growth. The phosphorylation of plectin at Ser4268 by Akt promotes its colocalization with vimentin and TNBC cell migration. Our findings underscore the importance of Akt3-plectin signaling as a potential TNBC therapeutic target.
    Keywords:  Biochemistry; Cancer; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113552
  13. Stem Cell Reports. 2025 Oct 16. pii: S2213-6711(25)00284-X. [Epub ahead of print] 102680
    mTORC2-mediated cell-cell interactions promote BMP4-induced WNT activation and mesoderm differentiation.
    Li Tong, Faiza Batool, Yueh-Ho Chiu, Priscilla Di Wu, Yudong Zhou, Xiaolun Ma, Santosh Atanur, Wei Cui.
      The mechanistic target of rapamycin complex 2 (mTORC2) is essential for embryonic development, but its underlying molecular mechanisms remain unclear. Here, we show that disruption of mTORC2 in human embryonic stem cells (hESCs) considerably alters the Rho/Rac signaling dynamics and reduces E-cadherin expression and cell adhesion. Despite this, mTORC2-deficient hESCs maintain self-renewal and expression of pluripotent markers when cultured in mouse embryonic fibroblast conditioned medium (MEF-CM) supplemented with bFGF. However, these hESCs exhibit significantly impaired mesoderm and endoderm differentiation in response to BMP4 and Activin treatment, respectively, possibly due to reduced WNT activation mediated by cell-cell interactions. Direct activation of the WNT pathway using a GSK3 inhibitor restores mesendoderm differentiation in mTORC2-deficient hESCs. Our study uncovers a novel mechanism by which mTORC2 regulates cell fate determination and highlights a critical link between the intercellular adhesion and the activation of canonical WNT genes.
    Keywords:  BMP4; WNT; cell adhesion; cell-cell interactions; gastrulation; human embryonic stem cells; mTORC2; mesoderm/endoderm differentiation
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102680
  14. Mol Cancer Res. 2025 Oct 13.
    Combined MYC Activation and PTEN Loss Drives Molecular Features of Aggressive Preinvasive Lesions in Mouse Prostate.
    Michael Rubenstein, Apurv Rege, Gretchen Hubbard, Danielle Cannady, Shreya Agarwal, Kevin Chen, Alex Estrada, Carolina Gomes Alexandre, Jessica Hicks, Tracy Jones, Qizhi Zheng, Srinivasan Yegnasubramanian, Charles J Bieberich, Angelo M De Marzo.
      Prostate cancer ranges from indolent to rapidly progressive. An elevated cell proliferation index portends poor outcomes, yet the molecular alterations essential for increased cell proliferation remain ill-defined. Gain of MYC combined with biallelic PTEN loss predicts prostate cancer mortality. Prior studies have shown that combined MYC overexpression and Pten loss, driven by the Hoxb13 locus, results in prostatic intraepithelial neoplastic (PIN) lesions that progress to metastatic disease (BMPC mice). Yet, single gene alterations in these mice result only in PIN. Herein, we performed transcriptomic profiling of PIN lesions from each of the 3 genotypes. While MYC alone resulted in increases in genes related to cell cycle regulation/cell division, combined MYC and Pten loss led to a further and more consistent increase, and a synergistic cell cycle progression. Increased ribosome biogenesis/translation are required for cell proliferation. While MYC alone increased 45S rRNA, and most components of the translation machinery, these were more strongly induced in BMPC mice. Surprisingly, Pten loss alone resulted in a downregulation of translation machinery genes, which could explain the absence of biallelic PTEN loss in human PIN and early carcinomas. Some MYC targets were increased only after Pten loss, indicating Pten loss increases MYC activity. Implications: These findings are that increased cell cycle and translational machinery gene induction may explain the synergy between MYC and PTEN loss for increasing prostate cancer cell proliferation and disease aggressiveness. Finally, these results provide further support for the therapeutic targeting of translation in prostate cancer.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-24-1206
  15. Bioinform Adv. 2025 ;5(1): vbaf237
    sc2DAT: workflow for targeting tumor subpopulations of single cells.
    Giacomo B Marino, Anna I Byrd, Nasheath Ahmed, Daniel J B Clarke, Avi Ma'ayan.
       Summary: The rapid increase in volume, diversity, and quality of single-cell omics profiling opens new opportunities for drug and target discovery. While there are already many workflows developed for analysis and visualization of data collected with single-cell RNA-seq, few workflows output ranked drugs and targets specific for subpopulation of single cells. Here, we present the single cells to drugs and targets (sc2DAT) workflow, a web-based software application for predicting cell surface targets and therapeutic compounds tailored to target-specific cell types automatically identified from scRNA-seq and bulk RNA-seq datasets. sc2DAT can be used to develop hypotheses about selectively eliminating malignant subpopulation of cells in cancer, or reprogram disease tissues toward a healthier phenotype using compounds from the LINCS L1000 dataset. Such compounds are hypothesized to either reverse or mimic the direction of changes in gene expression signatures, restoring the subpopulation of cells towards a healthier phenotype.
    Availability and implementation: sc2DAT is available from: https://sc2dat.maayanlab.cloud; the source code is available from: https://github.com/MaayanLab/sc2DAT.
    DOI:  https://doi.org/10.1093/bioadv/vbaf237
  16. Cancer Res. 2025 Oct 15.
    A Roadmap for the Future of Systems Biology in Cancer Research.
    H Steven Wiley, Carlos F Lopez, Andrei S Rodin, Russell C Rockne, Thomas E Yankeelov, Herbert M Sauro, Ghmkin Hassan, Sandhya Prabhakaran, Emek Demir, Mengzhou Hu, Juan Fuxman Bass, Kimberly A Luddy, Hannah Newman, Jonathan P Mochel, James C Costello, Jianhua Xing, Said M Afify, Ahmet Acar, Melanie Hayden Gephart, Song Feng, Orion Banks, Jineta Banerjee, Ashley Clayton, David E Hill, Randy F Sweis, Maxine C Umeh-Garcia, Yapeng Su, Aaron S Meyer.
      Cancer systems biology seeks to understand how cancer arises as a system of interconnected molecules, cells, and tissues, with the goal of understanding, predicting, and controlling the disease. In the last decade, the field has rapidly grown as advances in experimental, computational, and analytical technologies have improved our ability to capture and recapitulate the complexities of cancer at multiple scales. However, the field's promise to understand how specific molecular changes give rise to altered cancer outcomes remains incompletely fulfilled. Fortunately, an opportunity exists to accelerate progress by better coordinating modeling and data-gathering efforts across the cancer systems biology community. This will create the foundation for building accurate, multiscale cancer models that can better predict and identify improved therapeutic interventions. Here, we outline some of the current challenges in cancer systems biology research, how they can be addressed, and actions that the community can take to accelerate progress in the field.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0700
  17. J Biol Chem. 2025 Oct 14. pii: S0021-9258(25)02673-0. [Epub ahead of print] 110821
    Embryonic stem cell-derived extracellular vesicles delay cellular senescence by inhibiting oxidative stress.
    Shun Enomoto, Yun Ha Hur, Tatiana Solodova, Jacob Neumann, Richard A Cerione, Marc A Antonyak.
      The accumulation of cells that permanently exit the cell cycle and undergo senescence is a hallmark of aging and predisposes organisms to disease. Emerging evidence suggests extracellular vesicles (EVs) released by pluripotent embryonic stem cells (ESCs) possess therapeutic/regenerative properties with the potential to significantly impact cellular senescence and aging-related disorders. However, the critical next step for taking advantage of the potential benefits offered by ESC-derived EVs will be to unravel the molecular mechanisms responsible for their unique functional effects, which thus far have not been fully defined. Toward that goal, we now identify a signaling pathway essential for EVs shed by ESCs to potently block fibroblasts and astrocytes from undergoing senescence. It starts with the extracellular matrix protein fibronectin that coats the surfaces of EVs, enabling the vesicles to bind integrins on cells and trigger the activation of FAK and AKT. This leads to the inhibition of GSK3β activity and stabilization of the transcription factor Nrf2, which counteracts the effects of oxidative stress that would otherwise drive cellular senescence. These findings define a signaling pathway used by ESC-derived EVs to extend cellular lifespan, highlighting their potential application in anti-aging strategies.
    Keywords:  cell signaling; cellular senescence; exosome; extracellular vesicles; fibronectin; glycogen synthase kinase 3 (GSK-3); microvesicles; oxidative stress; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.jbc.2025.110821
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒20 at 21:56.