bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024–09–01
sixteen papers selected by
Xiao Qin, University of Oxford
  1. A structural learning method to uncover how information between single cells flows.
  2. Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate.
  3. Inferring pattern-driving intercellular flows from single-cell and spatial transcriptomics.
  4. Bottom-up or Top-down: Inflammation Reprograms Paneth Cells to Develop Bowel Cancers.
  5. Single-cell atlas defines distinct immune escape mechanisms in colorectal cancer.
  6. Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer.
  7. Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer.
  8. Toward a foundation model of causal cell and tissue biology with a Perturbation Cell and Tissue Atlas.
  9. Factors Determining Epithelial-Mesenchymal Transition in Cancer Progression.
  10. FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia.
  11. Unleashing the power of biomaterials to enhance organoid differentiation and function.
  12. Recovering biomolecular network dynamics from single-cell omics data requires three time points.
  13. A Novel Soft and Inflatable Strain-based Tactile Sensing Balloon for Enhanced Diagnosis of Colorectal Cancer Polyps Via Colonoscopy.
  14. Gastrointestinal Cancer Patient Derived Organoids at the Frontier of Personalized Medicine and Drug Screening.
  15. What tool or method do you wish existed?
  16. Spatiotemporal omics for biology and medicine.
  1. Nat Methods. 2024 Aug 26.
    A structural learning method to uncover how information between single cells flows.
      
    DOI:  https://doi.org/10.1038/s41592-024-02381-9
  2. bioRxiv. 2024 Aug 17. pii: 2024.08.14.607813. [Epub ahead of print]
    Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate.
    Jesse S Handler, Zijie Li, Rachel K Dveirin, Weixiang Fang, Hani Goodarzi, Elana J Fertig, Reza Kalhor.
      Identifying the key molecular pathways that enable metastasis by analyzing the eventual metastatic tumor is challenging because the state of the founder subclone likely changes following metastatic colonization. To address this challenge, we labeled primary mouse pancreatic ductal adenocarcinoma (PDAC) subclones with DNA barcodes to characterize their pre-metastatic state using ATAC-seq and RNA-seq and determine their relative in vivo metastatic potential prospectively. We identified a gene signature separating metastasis-high and metastasis-low subclones orthogonal to the normal-to-PDAC and classical-to-basal axes. The metastasis-high subclones feature activation of IL-1 pathway genes and high NF-κB and Zeb/Snail family activity and the metastasis-low subclones feature activation of neuroendocrine, motility, and Wnt pathway genes and high CDX2 and HOXA13 activity. In a functional screen, we validated novel mediators of PDAC metastasis in the IL-1 pathway, including the NF-κB targets Fos and Il23a, and beyond the IL-1 pathway including Myo1b and Tmem40. We scored human PDAC tumors for our signature of metastatic potential from mouse and found that metastases have higher scores than primary tumors. Moreover, primary tumors with higher scores are associated with worse prognosis. We also found that our metastatic potential signature is enriched in other human carcinomas, suggesting that it is conserved across epithelial malignancies. This work establishes a strategy for linking cancer cell state to future behavior, reveals novel functional regulators of PDAC metastasis, and establishes a method for scoring human carcinomas based on metastatic potential.
    DOI:  https://doi.org/10.1101/2024.08.14.607813
  3. Nat Methods. 2024 Aug 26.
    Inferring pattern-driving intercellular flows from single-cell and spatial transcriptomics.
    Axel A Almet, Yuan-Chen Tsai, Momoko Watanabe, Qing Nie.
      From single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST), one can extract high-dimensional gene expression patterns that can be described by intercellular communication networks or decoupled gene modules. These two descriptions of information flow are often assumed to occur independently. However, intercellular communication drives directed flows of information that are mediated by intracellular gene modules, in turn triggering outflows of other signals. Methodologies to describe such intercellular flows are lacking. We present FlowSig, a method that infers communication-driven intercellular flows from scRNA-seq or ST data using graphical causal modeling and conditional independence. We benchmark FlowSig using newly generated experimental cortical organoid data and synthetic data generated from mathematical modeling. We demonstrate FlowSig's utility by applying it to various studies, showing that FlowSig can capture stimulation-induced changes to paracrine signaling in pancreatic islets, demonstrate shifts in intercellular flows due to increasing COVID-19 severity and reconstruct morphogen-driven activator-inhibitor patterns in mouse embryogenesis.
    DOI:  https://doi.org/10.1038/s41592-024-02380-w
  4. Cancer Res. 2024 Aug 26.
    Bottom-up or Top-down: Inflammation Reprograms Paneth Cells to Develop Bowel Cancers.
    Julian Chua, Alex Gregorieff, Arshad Ayyaz.
      The origins of colorectal cancer (CRC) have long been a subject of intense debate. Early observations noted cancer formation in the human gut slightly above the base of crypts, the structural and functional units of the regenerative compartment of the intestinal epithelium. This suggested that the cells of origin for CRC reside close to the crypt-villus junction, where more differentiated cells are located. However, the specific induction of early cancer-initiating mutations within differentiated cells failed to initiate cancer. The subsequent identification of long-lived Lgr5+ intestinal stem cells and investigations into their role in cancer development further shifted the earlier views, leading to the widely accepted theory that CRC arises from stem cells and progenitors located at the base of crypts. A recent study published in Nature Genetics by Mathijs P. Verhagen and colleagues challenges this paradigm, providing compelling evidence that differentiated non-stem cell lineages, particularly Paneth cells, can serve as a source of intestinal tumorigenesis, especially in the context of inflammation and the consumption of a Western-style diet. This work significantly advances our understanding of the CRC initiation process and provides a new paradigm that may explain the increasingly higher incidence of CRC in younger people.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3073
  5. Nat Cancer. 2024 Aug 23.
    Single-cell atlas defines distinct immune escape mechanisms in colorectal cancer.
      
    DOI:  https://doi.org/10.1038/s43018-024-00809-x
  6. Nat Immunol. 2024 Aug 23.
    Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer.
    Christine Yiwen Yeh, Karmen Aguirre, Olivia Laveroni, Subin Kim, Aihui Wang, Brooke Liang, Xiaoming Zhang, Lucy M Han, Raeline Valbuena, Michael C Bassik, Young-Min Kim, Sylvia K Plevritis, Michael P Snyder, Brooke E Howitt, Livnat Jerby.
      The drivers of immune evasion are not entirely clear, limiting the success of cancer immunotherapies. Here we applied single-cell spatial and perturbational transcriptomics to delineate immune evasion in high-grade serous tubo-ovarian cancer. To this end, we first mapped the spatial organization of high-grade serous tubo-ovarian cancer by profiling more than 2.5 million cells in situ in 130 tumors from 94 patients. This revealed a malignant cell state that reflects tumor genetics and is predictive of T cell and natural killer cell infiltration levels and response to immune checkpoint blockade. We then performed Perturb-seq screens and identified genetic perturbations-including knockout of PTPN1 and ACTR8-that trigger this malignant cell state. Finally, we show that these perturbations, as well as a PTPN1/PTPN2 inhibitor, sensitize ovarian cancer cells to T cell and natural killer cell cytotoxicity, as predicted. This study thus identifies ways to study and target immune evasion by linking genetic variation, cell-state regulators and spatial biology.
    DOI:  https://doi.org/10.1038/s41590-024-01943-5
  7. Nat Commun. 2024 Aug 28. 15(1): 7414
    Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer.
    Mindy K Graham, Rulin Wang, Roshan Chikarmane, Bulouere Abel, Ajay Vaghasia, Anuj Gupta, Qizhi Zheng, Jessica Hicks, Polina Sysa-Shah, Xin Pan, Nicole Castagna, Jianyong Liu, Jennifer Meyers, Alyza Skaist, Yan Zhang, Michael Rubenstein, Kornel Schuebel, Brian W Simons, Charles J Bieberich, William G Nelson, Shawn E Lupold, Theodore L DeWeese, Angelo M De Marzo, Srinivasan Yegnasubramanian.
      How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.
    DOI:  https://doi.org/10.1038/s41467-024-51450-2
  8. Cell. 2024 Aug 22. pii: S0092-8674(24)00829-8. [Epub ahead of print]187(17): 4520-4545
    Toward a foundation model of causal cell and tissue biology with a Perturbation Cell and Tissue Atlas.
    Jennifer E Rood, Anna Hupalowska, Aviv Regev.
      Comprehensively charting the biologically causal circuits that govern the phenotypic space of human cells has often been viewed as an insurmountable challenge. However, in the last decade, a suite of interleaved experimental and computational technologies has arisen that is making this fundamental goal increasingly tractable. Pooled CRISPR-based perturbation screens with high-content molecular and/or image-based readouts are now enabling researchers to probe, map, and decipher genetically causal circuits at increasing scale. This scale is now eminently suitable for the deployment of artificial intelligence and machine learning (AI/ML) to both direct further experiments and to predict or generate information that was not-and sometimes cannot-be gathered experimentally. By combining and iterating those through experiments that are designed for inference, we now envision a Perturbation Cell Atlas as a generative causal foundation model to unify human cell biology.
    DOI:  https://doi.org/10.1016/j.cell.2024.07.035
  9. Int J Mol Sci. 2024 Aug 17. pii: 8972. [Epub ahead of print]25(16):
    Factors Determining Epithelial-Mesenchymal Transition in Cancer Progression.
    Paulina Tomecka, Dominika Kunachowicz, Julia Górczyńska, Michał Gebuza, Jacek Kuźnicki, Katarzyna Skinderowicz, Anna Choromańska.
      Epithelial-mesenchymal transition (EMT) is a process in which an epithelial cell undergoes multiple modifications, acquiring both morphological and functional characteristics of a mesenchymal cell. This dynamic process is initiated by various inducing signals that activate numerous signaling pathways, leading to the stimulation of transcription factors. EMT plays a significant role in cancer progression, such as metastasis and tumor heterogeneity, as well as in drug resistance. In this article, we studied molecular mechanisms, epigenetic regulation, and cellular plasticity of EMT, as well as microenvironmental factors influencing this process. We included both in vivo and in vitro models in EMT investigation and clinical implications of EMT, such as the use of EMT in curing oncological patients and targeting its use in therapies. Additionally, this review concludes with future directions and challenges in the wide field of EMT.
    Keywords:  cancer; cellular plasticity; epithelial-mesenchymal transition; regulatory factors; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25168972
  10. Dev Cell. 2024 Aug 22. pii: S1534-5807(24)00483-0. [Epub ahead of print]
    FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia.
    Alina L Li, Kensuke Sugiura, Noriyuki Nishiwaki, Kensuke Suzuki, Dorsay Sadeghian, Jun Zhao, Anirban Maitra, David Falvo, Rohit Chandwani, Jason R Pitarresi, Peter A Sims, Anil K Rustgi.
      Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during KrasG12D acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D. Using a gene regulatory network and pseudotime trajectory inferred from single-nuclei ATAC-seq and bulk RNA sequencing (RNA-seq), we hypothesized a regulatory model of the acinar-ADM-pancreatic intraepithelial neoplasia (PanIN) continuum and experimentally validated that Fosl1 knockout mice are delayed in the onset of ADM and neoplastic transformation. Our study also identifies that pro-inflammatory cytokines, such as granulocyte colony stimulating factor (G-CSF), can regulate FRA1 activity to modulate ADM. Our findings identify that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation.
    Keywords:  FRA1; G-CSF; KRAS; PanIN; acinar-ductal metaplasia; pancreatic ductal adenocarcinoma; pancreatitis
    DOI:  https://doi.org/10.1016/j.devcel.2024.07.021
  11. Nat Methods. 2024 Aug 23.
    Unleashing the power of biomaterials to enhance organoid differentiation and function.
    Samira Musah, Hamidreza Arzaghi.
      
    DOI:  https://doi.org/10.1038/s41592-024-02393-5
  12. NPJ Syst Biol Appl. 2024 Aug 27. 10(1): 97
    Recovering biomolecular network dynamics from single-cell omics data requires three time points.
    Shu Wang, Muhammad Ali Al-Radhawi, Douglas A Lauffenburger, Eduardo D Sontag.
      Single-cell omics technologies can measure millions of cells for up to thousands of biomolecular features, enabling data-driven studies of complex biological networks. However, these high-throughput experimental techniques often cannot track individual cells over time, thus complicating the understanding of dynamics such as time trajectories of cell states. These "dynamical phenotypes" are key to understanding biological phenomena such as differentiation fates. We show by mathematical analysis that, in spite of high dimensionality and lack of individual cell traces, three time-points of single-cell omics data are theoretically necessary and sufficient to uniquely determine the network interaction matrix and associated dynamics. Moreover, we show through numerical simulations that an interaction matrix can be accurately determined with three or more time-points even in the presence of sampling and measurement noise typical of single-cell omics. Our results can guide the design of single-cell omics time-course experiments, and provide a tool for data-driven phase-space analysis.
    DOI:  https://doi.org/10.1038/s41540-024-00424-7
  13. IEEE Sens J. 2024 Aug 15. 24(16): 26564-26573
    A Novel Soft and Inflatable Strain-based Tactile Sensing Balloon for Enhanced Diagnosis of Colorectal Cancer Polyps Via Colonoscopy.
    Mohammad Rafiee Javazm, Ozdemir Can Kara, Farshid Alambeigi.
      In this paper, with the goal of addressing the lack of tactile feedback in colorectal cancer (CRC) polyps diagnosis using a colonoscopy procedure, we propose the design and fabrication of a novel soft and inflatable strain-based tactile sensing balloon (SI-STSB). The proposed soft sensor features a unique stretchable sensing layer - that utilizes a liquid metal injected within spiral-shape microchannels of a stretchable substrate - and is integrated with a unique inflatable balloon mechanism. The proposed SI-STSB has been thoroughly characterized through different calibration experiments. Results demonstrate a phenomenal adjustable sensitivity with low hysteresis behavior under different experimental conditions for this sensor making it a great candidate for enhancing the existing diagnosis procedures.
    Keywords:  Colonoscopy; Inflatable Strain Sensor; Interaction Force; Tactile Sensing
    DOI:  https://doi.org/10.1109/jsen.2024.3423773
  14. Cells. 2024 Aug 06. pii: 1312. [Epub ahead of print]13(16):
    Gastrointestinal Cancer Patient Derived Organoids at the Frontier of Personalized Medicine and Drug Screening.
    Zhenjie Yang, Jun Yu, Chi Chun Wong.
      Cancer is a leading cause of death worldwide. Around one-third of the total global cancer incidence and mortality are related to gastrointestinal (GI) cancers. Over the past few years, rapid developments have been made in patient-derived organoid (PDO) models for gastrointestinal cancers. By closely mimicking the molecular properties of their parent tumors in vitro, PDOs have emerged as powerful tools in personalized medicine and drug discovery. Here, we review the current literature on the application of PDOs of common gastrointestinal cancers in the optimization of drug treatment strategies in the clinic and their rising importance in pre-clinical drug development. We discuss the advantages and limitations of gastrointestinal cancer PDOs and outline the microfluidics-based strategies that improve the throughput of PDO models in order to extract the maximal benefits in the personalized medicine and drug discovery process.
    Keywords:  drug screening; gastrointestinal cancer; patient-derived organoids; personalized medicine
    DOI:  https://doi.org/10.3390/cells13161312
  15. Cell. 2024 Aug 22. pii: S0092-8674(24)00837-7. [Epub ahead of print]187(17): 4433-4438
    What tool or method do you wish existed?
    Yvonne Y Chen, Charles L Evavold, Matthias Mann, Emily R Davenport, Margaret McFall-Ngai, Magda Bienko, Hiroki R Ueda, Lin Tian, Nikki Tjahjono, Polina Anikeeva, Jun-Jie Gogo Liu, Tara L Deans, Xiaohua Shen.
      We asked researchers from a range of disciplines across biology, engineering, and medicine to describe a current technological need. The goal is to provide a sample of the various technological gaps that exist and inspire future research projects.
    DOI:  https://doi.org/10.1016/j.cell.2024.07.043
  16. Cell. 2024 Aug 22. pii: S0092-8674(24)00834-1. [Epub ahead of print]187(17): 4488-4519
    Spatiotemporal omics for biology and medicine.
    Longqi Liu, Ao Chen, Yuxiang Li, Jan Mulder, Holger Heyn, Xun Xu.
      The completion of the Human Genome Project has provided a foundational blueprint for understanding human life. Nonetheless, understanding the intricate mechanisms through which our genetic blueprint is involved in disease or orchestrates development across temporal and spatial dimensions remains a profound scientific challenge. Recent breakthroughs in cellular omics technologies have paved new pathways for understanding the regulation of genomic elements and the relationship between gene expression, cellular functions, and cell fate determination. The advent of spatial omics technologies, encompassing both imaging and sequencing-based methodologies, has enabled a comprehensive understanding of biological processes from a cellular ecosystem perspective. This review offers an updated overview of how spatial omics has advanced our understanding of the translation of genetic information into cellular heterogeneity and tissue structural organization and their dynamic changes over time. It emphasizes the discovery of various biological phenomena, related to organ functionality, embryogenesis, species evolution, and the pathogenesis of diseases.
    DOI:  https://doi.org/10.1016/j.cell.2024.07.040
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