bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–06–29
twelve papers selected by
Xiao Qin, University of Oxford
  1. Innate immunity and the NF-κB pathway control prostate stem cell plasticity, reprogramming and tumor initiation.
  2. Rescuing dendritic cell interstitial motility sustains antitumour immunity.
  3. Hallmarks of stem cell aging.
  4. High throughput single-cell proteomics of in vivo cells.
  5. Hyper-responsiveness of cancer stem cells to microenvironmental cues controls metastasis and therapy response through YAP/TAZ/TEAD.
  6. Mapping cancer gene dynamics through state-specific interactions.
  7. Barcoded viral tracing identifies immunosuppressive astrocyte-glioma interactions.
  8. Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression.
  9. Gene context drift identifies drug targets to mitigate cancer treatment resistance.
  10. The cellular substrate of evolutionary novelty.
  11. Virtual Cell Challenge: Toward a Turing test for the virtual cell.
  12. Can AI build a virtual cell? Scientists race to model life's smallest unit.
  1. Nat Cancer. 2025 Jun 23.
    Innate immunity and the NF-κB pathway control prostate stem cell plasticity, reprogramming and tumor initiation.
    Chen Jiang, Yura Song, Sandrine Rorive, Justine Allard, Elisavet Tika, Zahra Zahedi, Christine Dubois, Isabelle Salmon, Alejandro Sifrim, Cédric Blanpain.
      Prostate epithelium develops from multipotent stem cells, which are replaced in adult life by different lineage-restricted basal and luminal unipotent stem cells. Deletion of Pten re-induces multipotency in basal cells (BCs); however, the molecular mechanisms regulating BC plasticity and tumor initiation are poorly understood. Here we showed that Pten deletion in BCs led to distinct cell fate reprogramming and tumor initiation in a regionalized manner. Single-cell RNA sequencing, ATAC-seq and in situ characterization revealed that following Pten deletion in anterior and dorsolateral prostates, BCs were highly plastic and reprogrammed into a hillock-like state, progressing into a proximal-like luminal state before giving rise to invasive tumors. This BC reprogramming was associated with the activation of innate immunity. Pharmacological targeting of interleukin-1, JAK-STAT and NF-κB as well as genetic deletion of Nfkb inhibit Pten-induced cell plasticity and reprogramming in a cellular autonomous manner, opening new opportunities for prevention and treatment of prostate cancer.
    DOI:  https://doi.org/10.1038/s43018-025-00994-3
  2. Nature. 2025 Jun 25.
    Rescuing dendritic cell interstitial motility sustains antitumour immunity.
    Haichao Tang, Zongfang Wei, Bei Zheng, Yumeng Cai, Peihan Wu, Lulu Wu, Xiaohe Ma, Yanqin Chen, Si Su, Jinmin Xu, Yu Qiao, Ying Zhang, Juju Miao, Zijing Yu, Yaodong Zhao, Zhen Xia, Rongjing Zhou, Jian Liu, Jufeng Guo, Zhaoyuan Liu, Qi Xie, Florent Ginhoux, Luming Zhao, Xu Li, Bing Xia, Huanwen Wu, Yongdeng Zhang, Ting Zhou.
      The dendritic cell (DC)-initiated and sustained cancer immunity cycle is indispensable for effective endogenous and therapeutically mobilized antitumour T cell responses1-8. This necessitates the continuous migration of antigen-carrying DCs from the tumour microenvironment (TME) to the tumour draining lymph nodes (tdLNs)7-13. Here, through longitudinal analysis of human and mouse tumours, we observed a progressive decrease in migratory conventional DCs (mig-cDCs) in the tdLNs during tumour progression. This decline compromised tumour-specific T cell priming and subsequent T cell supply to the TME. Using a genome-wide in vivo CRISPR screen, we identified phosphodiesterase 5 (PDE5) and its substrate cyclic guanosine monophosphate (cGMP) as key modulators of DC migration. Advanced tumours disrupted cGMP synthesis in DCs to decrease their motility, while PDE5 perturbation preserved the cGMP pool to restore DC migration. Mechanistically, cGMP enhanced myosin-II activity through Rho-associated factors, extending the paradigm of cGMP-regulated amoeboid migration from Dictyostelium to mammalian immune cells. Pharmacological inhibition of PDE5 using sildenafil restored mig-cDC homing to late-stage tdLNs and sustained antitumour immunity in a DC-dependent manner. Our findings bridge fundamental DC interstitial motility to antitumour immunity, revealing that its disruption in chaotic TME promotes immune evasion, and its enhancement offers a promising direction for DC-centric immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-09202-9
  3. Cell Stem Cell. 2025 Jun 17. pii: S1934-5909(25)00226-7. [Epub ahead of print]
    Hallmarks of stem cell aging.
    Thomas A Rando, Anne Brunet, Margaret A Goodell.
      As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.
    Keywords:  aging; differentiation; hematopoietic stem cells; heterogeneity; muscle stem cells; neural stem cells; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.06.004
  4. Mol Cell Proteomics. 2025 Jun 20. pii: S1535-9476(25)00117-3. [Epub ahead of print] 101018
    High throughput single-cell proteomics of in vivo cells.
    Shiri Karagach, Joachim Smollich, Ofir Atrakchi, Vishnu Mohan, Tamar Geiger.
      Single-cell mass spectrometry-based proteomics (SCP) can resolve cellular heterogeneity in complex biological systems and provide a system-level view of the proteome of each cell. Major advancements in SCP methodologies have been introduced in recent years, providing highly sensitive sample preparation methods and mass spectrometric technologies. However, most studies present limited throughput and mainly focus on the analysis of cultured cells. To enhance the depth, accuracy, and throughput of SCP for tumor analysis, we developed an automated, high-throughput pipeline that enables the analysis of 1,536 single cells in a single experiment. This approach integrates low-volume sample preparation, automated sample purification, and LC-MS analysis with the Slice-PASEF method. Integration of these methodologies into a streamlined pipeline led to a robust and reproducible identification of more than 3000 proteins per cell. We applied this pipeline to analyze tumor macrophages in a murine lung metastasis model. We identified over 1,700 proteins per cell, including key macrophage markers and more than 500 differentially expressed proteins between tumor and control macrophages. PCA analysis successfully separated these populations, revealing the utility of SCP in capturing biologically relevant signals in the tumor microenvironment. Our results demonstrate a robust and scalable pipeline poised to advance single-cell proteomics in cancer research.
    DOI:  https://doi.org/10.1016/j.mcpro.2025.101018
  5. bioRxiv. 2025 Mar 15. pii: 2025.03.13.643008. [Epub ahead of print]
    Hyper-responsiveness of cancer stem cells to microenvironmental cues controls metastasis and therapy response through YAP/TAZ/TEAD.
    Binwu Tang, Jacob Minin, Victoria Gonzalez, Zoya Khan, Yuval Raviv, Yu-An Yang, Christine Carney, Zachary Millman, Daniel Grun, Cristiana Pineda, Alina Sharma, Dominic Esposito, Hualong Yan, Jing Huang, Andy D Tran, Michael Kruhlak, Howard Yang, Maxwell P Lee, Lalage M Wakefield.
      Cancer stem cells (CSCs) are key drivers of metastasis and therapy resistance but have been challenging to visualize and study in situ . Using a fluorescent CSC reporter, we observed very different population dynamics for CSCs and nonCSCs during metastatic lung colonization in breast cancer models. CSC expansive self-renewal drives early lesion formation before switching to a maintenance mode of balanced self-renewal and differentiation, whereupon nonCSC proliferation takes over as the main driver of metastatic expansion. Mechanistic analyses showed that CSCs are hyper-responsive to microenvironmental cues such as cell crowding and nutrient availability, suggesting a novel role for CSCs as sensors and early responders to fluctuating local conditions in the tumor. Incoming signals converge on YAP/TAZ/TEAD, with heightened CSC sensitivity and response supported by elevated receptor expression and increased chromatin accessibility around enhancers with TEAD binding sites. Targeting inputs to the YAP/TAZ/TEAD node reversed chemotherapy-induced enrichment of CSCs in lung metastases.
    Highlights: Different population dynamics for breast cancer stem cells (CSCs) and their differentiated progeny in early metastatic colonizationCSCs are hyper-responsive to microenvironmental cues and serve as sensors of local conditions for the tumorMany microenvironmental inputs converge on YAP/TAZ to regulate self-renewal vs differentiation fate decisions in the CSCTargeting YAP/TAZ input pathways blocks chemotherapy-induced enrichment of CSCs.
    DOI:  https://doi.org/10.1101/2025.03.13.643008
  6. Cell Rep. 2025 Jun 20. pii: S2211-1247(25)00643-6. [Epub ahead of print]44(7): 115872
    Mapping cancer gene dynamics through state-specific interactions.
    Adrián Maqueda-Real, Laia Ollé-Monràs, Solip Park.
      Metastatic cancer, a major cause of mortality, has been understudied compared to primary tumors, leaving gaps in our understanding of how cancer genes adapt between these states. We analyzed the association between mutations and copy number alterations in 25,000 tumor samples from both primary and metastatic cancers. Our findings show that cancer genes display distinct interaction strengths across these states, with 27.45% of genes, including ARID1A, FBXW7, and SMARCA4, shifting between one-hit and two-hit drivers. Interaction strengths varied by cancer state and treatment conditions, revealing seven state-specific interactions. We also identified 38 primary-specific and 21 metastatic-specific high-order interactions, enriched in cancer hallmarks, indicating unique tumor progression mechanisms. These findings highlight dynamic tumor progression mechanisms and underscore the importance of considering cancer state in research and treatment strategies for precise therapeutic interventions.
    Keywords:  CP: Cancer; CP: Genomics; cancer fitness; cancer genomics; cancer state; high-order interaction; metastasis; state-specific genetic interaction; survival analysis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115872
  7. Nature. 2025 Jun 25.
    Barcoded viral tracing identifies immunosuppressive astrocyte-glioma interactions.
    Brian M Andersen, Camilo Faust Akl, Michael A Wheeler, Zhaorong Li, Martin Diebold, Michael Kilian, Joseph M Rone, Aditya Misra, Jessica E Kenison, Joon-Hyuk Lee, Hong-Gyun Lee, Carolina M Polonio, David Merrell, Jakob H Weiss, Lillie Godinez, Gavin Piester, Tomer Illouz, Jessica J Ye, Arianna Ghia, Jazmin Martinez, Elizabeth N Chung, Lena Srun, Daniel Farrenkopf, Lucas E Flausino, Anton M Schüle, Liliana M Sanmarco, Federico Giovannoni, Luca Fehrenbacher, Marc Charabati, Cristina Gutiérrez-Vázquez, Margaret M Cusick, Prem S Prabhakar, Connor C Bossi, Emily Lapinskas, Roni Nowarski, Gad Getz, Keith L Ligon, Marco Prinz, E Antonio Chiocca, David A Reardon, Francisco J Quintana.
      Glioblastoma (GBM) is the most lethal primary brain malignancy1. Immunosuppression in the GBM tumour microenvironment (TME) is an important barrier to immune-targeted therapies, but our understanding of the mechanisms of immune regulation in the GBM TME is limited2. Here we describe a viral barcode interaction-tracing approach3 to analyse TME cell-cell communication in GBM clinical samples and preclinical models at single-cell resolution. We combine it with single-cell and bulk RNA-sequencing analyses, human organotypic GBM cultures, in vivo cell-specific CRISPR-Cas9-driven genetic perturbations as well as human and mouse experimental systems to identify an annexin A1-formyl peptide receptor 1 (ANXA1-FPR1) bidirectional astrocyte-GBM communication pathway that limits tumour-specific immunity. FPR1 inhibits immunogenic necroptosis in tumour cells, and ANXA1 suppresses NF-κB and inflammasome activation in astrocytes. ANXA1 expression in astrocytes and FPR1 expression in cancer cells are associated with poor outcomes in individuals with GBM. The inactivation of astrocyte-glioma ANXA1-FPR1 signalling enhanced dendritic cell, T cell and macrophage responses, increasing infiltration by tumour-specific CD8+ T cells and limiting T cell exhaustion. In summary, we have developed a method to analyse TME cell-cell interactions at single-cell resolution in clinical samples and preclinical models, and used it to identify bidirectional astrocyte-GBM communication through ANXA1-FPR1 as a driver of immune evasion and tumour progression.
    DOI:  https://doi.org/10.1038/s41586-025-09191-9
  8. Cancer Cell. 2025 Jun 20. pii: S1535-6108(25)00253-3. [Epub ahead of print]
    Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression.
    Lisa Schweizer, Hilary A Kenny, Rahul Krishnan, Lucy Kelliher, Agnes J Bilecz, Janna Heide, Leonhard Donle, Aasa Shimizu, Andreas Metousis, Rachelle Mendoza, Thierry M Nordmann, Sarah Rauch, Sabrina Richter, Yan Li, Florian A Rosenberger, Maximilian T Strauss, Katherine C Kurnit, Marvin Thielert, Edwin Rodriguez, Johannes B Müller-Reif, S Diane Yamada, Fabian J Theis, Andreas Mund, Ricardo R Lastra, Matthias Mann, Ernst Lengyel.
      Epithelial serous borderline tumors (SBT) are non-invasive neoplastic ovarian lesions that may recur as chemo-resistant low-grade serous cancer (LGSC). While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood. Here, we integrate cell-type resolved spatial proteomics and transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastases in both stroma and tumor. The transition occurs within the epithelial compartment through an intermediary stage with micropapillary features, during which LGSC overexpresses c-Met and several brain-specific proteins. Within the tumor microenvironment, interconnectivity between cancer and stromal cells, along with enzymes degrading a packed extracellular matrix, suggests functional collaboration among various cell types. We functionally validated 16 drug targets identified through integrated spatial transcriptomics and proteomics. Combined treatment targeting CDK4/6 (milciclib) and FOLR1 (mirvetuximab) achieved significant tumor reduction in vivo, representing a promising therapeutic strategy for LGSC.
    Keywords:  borderline tumor; deep visual proteomics; low-grade serous cancer; mass spectrometry; metastasis; ovarian cancer; pathology; proteomics; transcriptomics
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.004
  9. Cancer Cell. 2025 Jun 20. pii: S1535-6108(25)00255-7. [Epub ahead of print]
    Gene context drift identifies drug targets to mitigate cancer treatment resistance.
    Amir Jassim, Birgit V Nimmervoll, Sabrina Terranova, Erica Nathan, Linda Hu, Jessica T Taylor, Katherine E Masih, Lisa Ruff, Matilde Duarte, Elizabeth Cooper, Gunjan Katyal, Melika Akhbari, Reuben J Gilbertson, Jennifer C Coleman, Joseph S Toker, Colton Terhune, Gabriel Balmus, Stephen P Jackson, Hailong Liu, Tao Jiang, Michael D Taylor, Kui Hua, Jean E Abraham, Mariella G Filbin, Anthony Hill, Anarita Patrizi, Neil Dani, Aviv Regev, Maria K Lehtinen, Richard J Gilbertson.
      Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms -invisible to existing computational approaches- enabling the design of highly effective combination treatments for mice with choroid plexus carcinoma, and the prediction of potential new treatments for patients with medulloblastoma and triple-negative breast cancer. Thus, RECODR may unravel the complexity of cancer treatment resistance by detecting context-specific changes in gene interactions that determine the resistant phenotype.
    Keywords:  DNA repair; cancer; choroid plexus; choroid plexus carcinoma; combination therapy; graph networks; machine learning; radiation; treatment resistance; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.005
  10. Curr Biol. 2025 Jun 23. pii: S0960-9822(25)00443-9. [Epub ahead of print]35(12): R626-R637
    The cellular substrate of evolutionary novelty.
    Joseph Parker, Matt Pennell.
      A major challenge in biology is comprehending how complex multicellular novelties evolve. Central to this problem is explaining how qualitatively new phenotypic traits - typically the focus of comparative developmental and macroevolutionary studies above the species level - can become established through population genetic processes. Here, we suggest that a resolution may be found by acknowledging the fundamental entities from which functional organismal phenotypes are constructed. We argue that these are not genes, proteins or cell types, but rather gene expression programs (GEPs): sets of co-expressed transcripts that collectively encode cellular subfunctions. We advance that, because GEPs are the smallest, elemental functional units underlying phenotypes, it follows that they represent the substrate upon which population genetic processes must act to explain the origin of evolutionary novelty at the cellular level and above. Novelty arises through the evolution of novel GEPs, through novel synergisms between GEPs that become co-expressed within the same cell or through interactions between different GEPs juxtaposed in cooperating cells within organs. The revolution in single cell biology offers the chance to trace evolution at the resolution of GEPs in populations and across clades, potentially unifying our view of multicellular phenotypic evolution.
    DOI:  https://doi.org/10.1016/j.cub.2025.04.014
  11. Cell. 2025 Jun 26. pii: S0092-8674(25)00675-0. [Epub ahead of print]188(13): 3370-3374
    Virtual Cell Challenge: Toward a Turing test for the virtual cell.
    Yusuf H Roohani, Tony J Hua, Po-Yuan Tung, Lexi R Bounds, Feiqiao B Yu, Alexander Dobin, Noam Teyssier, Abhinav Adduri, Alden Woodrow, Brian S Plosky, Reshma Mehta, Benjamin Hsu, Jeremy Sullivan, Chiara Ricci-Tam, Nianzhen Li, Julia Kazaks, Luke A Gilbert, Silvana Konermann, Patrick D Hsu, Hani Goodarzi, Dave P Burke.
      Virtual cells are an emerging frontier at the intersection of artificial intelligence and biology. A key goal of these cell state models is predicting cellular responses to perturbations. The Virtual Cell Challenge is being established to catalyze progress toward this goal. This recurring and open benchmark competition from the Arc Institute will provide an evaluation framework, purpose-built datasets, and a venue for accelerating model development.
    DOI:  https://doi.org/10.1016/j.cell.2025.06.008
  12. Nature. 2025 Jun 27.
    Can AI build a virtual cell? Scientists race to model life's smallest unit.
    Ewen Callaway.
      
    Keywords:  Cell biology; Machine learning; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-02011-0
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