bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024–11–17
twenty papers selected by
Xiao Qin, University of Oxford
  1. Modeling adenoma-carcinoma progression from a single MLH1-knockout cell via colon organoids.
  2. Establishment of Patient-Derived Organoids from Colorectal Cancer Resection Samples.
  3. scPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases.
  4. Short circuit: Transcription factor addiction as a growing vulnerability in cancer.
  5. Systematic analysis identifies a connection between spatial and genomic variations of chromatin states.
  6. Pseudo-trajectory inference for identifying essential regulations and molecules in cell fate decisions.
  7. Single-cell 3D multi-omics during human brain development.
  8. Early-Onset Colorectal Cancer: Molecular Underpinnings Accelerating Occurrence.
  9. Unveiling the dynamics of circulating tumor cells in colorectal cancer: from biology to clinical applications.
  10. Tumor heterogeneity and cooperating cancer hallmarks driven by divergent EMT programs.
  11. Multimodal optical pooled screening with CRISPRmap.
  12. Learning the language of DNA.
  13. Normal tissue transcriptional signatures for tumor-type-agnostic phenotype prediction.
  14. Multiplexed multi-modal single cell technologies: From observation to perturbation analysis.
  15. DNA regulatory element cooperation and competition in transcription.
  16. Improving the identification of cancer driver modules using deep features learned from multi-omics data.
  17. Ex Vivo Intestinal Organoid Models: Current State-of-the-Art and Challenges in Disease Modelling and Therapeutic Testing for Colorectal Cancer.
  18. Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration.
  19. Multi-pass nanopore for single-molecule protein sequencing.
  20. Clinical functional proteomics of intercellular signalling in pancreatic cancer.
  1. Nat Cancer. 2024 Nov 08.
    Modeling adenoma-carcinoma progression from a single MLH1-knockout cell via colon organoids.
      
    DOI:  https://doi.org/10.1038/s43018-024-00842-w
  2. Methods Mol Biol. 2024 Nov 10.
    Establishment of Patient-Derived Organoids from Colorectal Cancer Resection Samples.
    Didem Seven, Szilvia Baron, Henner F Farin.
      Colorectal cancer (CRC) organoids can serve as powerful preclinical cell models that accurately reflect individual tumor characteristics. Establishing a patient-derived CRC biobank facilitates a wide range of applications, including basic oncology research, new drug discovery, drug testing, and personalized medicine. This chapter details the process of generation of organoids from surgical samples of primary and metastatic CRC as well as from tumor adjacent normal colon tissues. Furthermore, best practices for cultivation and cryostorage of CRC organoids are described.
    Keywords:  Biobank; Colon organoids; Colorectal cancer; Patient-derived organoids; Stem cells
    DOI:  https://doi.org/10.1007/7651_2024_575
  3. Nat Commun. 2024 Nov 15. 15(1): 9932
    scPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases.
    Hongru Hu, Gerald Quon.
      Multimodal single-cell assays profile multiple sets of features in the same cells and are widely used for identifying and mapping cell states between chromatin and mRNA and linking regulatory elements to target genes. However, the high dimensionality of input features and shallow sequencing depth compared to unimodal assays pose challenges in data analysis. Here we present scPair, a multimodal single-cell data framework that overcomes these challenges by employing an implicit feature selection approach. scPair uses dual encoder-decoder structures trained on paired data to align cell states across modalities and predict features from one modality to another. We demonstrate that scPair outperforms existing methods in accuracy and execution time, and facilitates downstream tasks such as trajectory inference. We further show scPair can augment smaller multimodal datasets with larger unimodal atlases to increase statistical power to identify groups of transcription factors active during different stages of neural differentiation.
    DOI:  https://doi.org/10.1038/s41467-024-53971-2
  4. Curr Opin Struct Biol. 2024 Nov 12. pii: S0959-440X(24)00175-1. [Epub ahead of print]89 102948
    Short circuit: Transcription factor addiction as a growing vulnerability in cancer.
    Molly Davies, Maeve Boyce, Eric Conway.
      Core regulatory circuitry refers to the network of lineage-specific transcription factors regulating expression of both their own coding genes, and that of other transcription factors. Such autoregulatory feedback loops coordinate the transcriptome and epigenome during development and cell fate decisions. This circuitry is hijacked during oncogenesis resulting in cancer cell fate being maintained by lineage-specific transcription factors. Major advances in functional genomics and chemical biology are paving the way for a new generation of cancer therapeutics aimed at disrupting this circuitry through both direct and indirect means. Here we review these critical advances in mechanistic understanding of transcription factor addiction in cancer and how the advent of proteolysis targeting chimeras and CRISPR screen assays are leading the way for a new paradigm in targeted cancer treatments.
    Keywords:  CRISPR screen; Cancer; Cancer dependency; Core regulatory circuitry; Epigenetics; Personalised medicine; Targeted therapy; Transcription factor; Transcription factor network; o'PROTAC; oligoTRAFTAC
    DOI:  https://doi.org/10.1016/j.sbi.2024.102948
  5. Cell Syst. 2024 Nov 06. pii: S2405-4712(24)00303-X. [Epub ahead of print]
    Systematic analysis identifies a connection between spatial and genomic variations of chromatin states.
    Xuan Cao, Terry Ma, Rong Fan, Guo-Cheng Yuan.
      Chromatin states play important roles in the maintenance of cell identities, yet their spatial patterns remain poorly characterized at the organism scale. We developed a systematic approach to analyzing spatial epigenomic data and then applied it to a recently published spatial-CUT&Tag dataset that was obtained from a mouse embryo. We identified a set of spatial genes whose H3K4me3 patterns delineate tissue boundaries. These genes are enriched with tissue-specific transcription factors, and their corresponding genomic loci are marked by broad H3K4me3 domains. Integrative analysis with H3K27me3 profiles showed coordinated spatial transitions across tissue boundaries, which is marked by the continuous shortening of H3K4me3 domains and expansion of H3K27me3 domains. Motif-based analysis identified transcription factors whose activities change significantly during such transitions. Taken together, our systematic analyses reveal a strong connection between the genomic and spatial variations of chromatin states. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  CUT&Tag; chromatin state; computational biology; development; epigenomics; spatial biology
    DOI:  https://doi.org/10.1016/j.cels.2024.10.006
  6. J Biol Phys. 2024 Nov 14. 51(1): 2
    Pseudo-trajectory inference for identifying essential regulations and molecules in cell fate decisions.
    Xinyu He, Ruoyu Tang, Jie Lou, Ruiqi Wang.
      Cell fate decision is crucial in biological development and plays fundamental roles in normal development and functional maintenance of organisms. By identifying key regulatory interactions and molecules involved in these fate decisions, we can shed light on the intricate mechanisms underlying the cell fates. This understanding ultimately reveals the fundamental principles driving biological development and the origins of various diseases. In this study, we present an overarching framework which integrates pseudo-trajectory inference and differential analysis to determine critical regulatory interactions and molecules during cell fate transitions. To demonstrate feasibility and reliability of the approach, we employ the differentiation networks of hepatobiliary system and embryonic stem cells as representative model systems. By applying pseudo-trajectory inference to biological data, we aim to identify critical regulatory interactions and molecules during the cell fate transition processes. Consistent with experimental observations, the approach can allow us to infer dynamical cell fate decision processes and gain insights into the underlying mechanisms which govern cell state decisions.
    Keywords:  Cell fate decisions; Differential analysis; Pseudo-trajectory extrapolation
    DOI:  https://doi.org/10.1007/s10867-024-09665-3
  7. Nat Genet. 2024 Nov;56(11): 2296
    Single-cell 3D multi-omics during human brain development.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-024-02008-x
  8. Cell Mol Gastroenterol Hepatol. 2024 Nov 05. pii: S2352-345X(24)00180-2. [Epub ahead of print] 101425
    Early-Onset Colorectal Cancer: Molecular Underpinnings Accelerating Occurrence.
    Atehkeng Zinkeng, F Lloyd Taylor, Samuel H Cheong, Heyu Song, Juanita L Merchant.
      The onset of colorectal cancer (CRC) in patients under 50 continues to rapidly increase. This study highlights the epidemiological changes, risk factors, clinical characteristics, and molecular profiles prevalent in early-onset colorectal cancer (EO-CRC) patients, and identifies key areas for future research. It has been noted that only a small fraction of EO-CRC cases is attributed to known hereditary mutations and fit the canonical pathway of late onset colorectal cancer (LOCRC) development. To highlight this, we review the genetic and epigenetic modifications specific to EO-CRC. We also discuss the synergetic effect of single nucleotide polymorphisms (SNPs) and environmental factors on the early onset of CRC. Additionally, we discuss the potential of non-invasive biomarker assays to enhance early detection, screening, diagnosis, and prognostic outcome predictions.
    Keywords:  DNA mutation; Epigenetics; Insulin signaling; Mature onset diabetes of the young; Microbiome; Non-hereditary; PI3K/AKT signaling pathway; Screening tools; Single nucleotide polymorphisms; Tumor Microenvironment; Wnt/β-catenin signaling
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.101425
  9. Front Cell Dev Biol. 2024 ;12 1498032
    Unveiling the dynamics of circulating tumor cells in colorectal cancer: from biology to clinical applications.
    Claudia Dompé, Aleksandra Chojnowska, Rodryg Ramlau, Michal Nowicki, Catherine Alix-Panabières, Joanna Budna-Tukan.
      This review delves into the pivotal role of circulating tumor cells (CTCs) in colorectal cancer (CRC) metastasis, focusing on their biological properties, interactions with the immune system, advanced detection techniques, and clinical implications. We explored how metastasis-competent CTCs evade immune surveillance and proliferate, utilizing cutting-edge detection and isolation technologies, such as microfluidic devices and immunological assays, to enhance sensitivity and specificity. The review highlights the significant impact of CTC interactions with immune cells on tumor progression and patient outcomes. It discusses the application of these findings in clinical settings, including non-invasive liquid biopsies for early diagnosis, prognosis, and treatment monitoring. Despite advancements, challenges remain, such as the need for standardized methods to consistently capture and analyze CTCs. Addressing these challenges through further molecular and cellular research on CTCs could lead to improved interventions and outcomes for CRC patients, underscoring the importance of unraveling the complex dynamics of CTCs in cancer progression.
    Keywords:  cancer cell biology; circulating tumor cells; colorectal cancer; liquid biopsy; metastasis
    DOI:  https://doi.org/10.3389/fcell.2024.1498032
  10. Cancer Res. 2024 Nov 15.
    Tumor heterogeneity and cooperating cancer hallmarks driven by divergent EMT programs.
    Phoebe Carter, Yibin Kang.
      Epithelial-to-mesenchymal transition (EMT) is known to play roles in orchestrating cellular plasticity across many physiological and pathological contexts. Partial EMT, wherein cells maintain both epithelial and mesenchymal features, is gaining recognition for its functional importance in cancer in recent years. There are many factors regulating both partial and full EMT, and the precise mechanisms underlying these processes vary depending on the biological context. Furthermore, how different EMT states cooperate to create a heterogeneous tumor population and promote different pro-malignant features remains largely undefined. In a recent study published in Nature Cancer, Youssef and colleagues described how two disparate EMT programs, active in either organ fibrosis or embryonic development, are utilized within different cells within the same murine mammary tumor model. This work provides mechanistic insight into the development of intratumoral heterogeneity, providing evidence for the cooperation between the two EMT trajectories.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4309
  11. Nat Genet. 2024 Nov;56(11): 2296
    Multimodal optical pooled screening with CRISPRmap.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-024-02010-3
  12. Science. 2024 Nov 15. 386(6723): 729-730
    Learning the language of DNA.
    Christina V Theodoris.
      A genomic foundation model broadly enables sequence modeling, prediction, and design.
    DOI:  https://doi.org/10.1126/science.adt3007
  13. Sci Rep. 2024 11 08. 14(1): 27230
    Normal tissue transcriptional signatures for tumor-type-agnostic phenotype prediction.
    Corey Weistuch, Kevin A Murgas, Jiening Zhu, Larry Norton, Ken A Dill, Allen R Tannenbaum, Joseph O Deasy.
      Cancer transcriptional patterns reflect both unique features and shared hallmarks across diverse cancer types, but whether differences in these patterns are sufficient to characterize the full breadth of tumor phenotype heterogeneity remains an open question. We hypothesized that these shared transcriptomic signatures reflect repurposed versions of functional tasks performed by normal tissues. Starting with normal tissue transcriptomic profiles, we use non-negative matrix factorization to derive six distinct transcriptomic phenotypes, called archetypes, which combine to describe both normal tissue patterns and variations across a broad spectrum of malignancies. We show that differential enrichment of these signatures correlates with key tumor characteristics, including overall patient survival and drug sensitivity, independent of clinically actionable DNA alterations. Additionally, we show that in HR+/HER2- breast cancers, metastatic tumors adopt transcriptomic signatures consistent with the invaded tissue. Broadly, our findings suggest that cancer often arrogates normal tissue transcriptomic characteristics as a component of both malignant progression and drug response. This quantitative framework provides a strategy for connecting the diversity of cancer phenotypes and could potentially help manage individual patients.
    Keywords:  Cancer ecology and evolution; Drug sensitivity prediction; Metastatic breast cancer; Molecular profiling; Prognosis
    DOI:  https://doi.org/10.1038/s41598-024-76625-1
  14. Mol Cells. 2024 Nov 08. pii: S1016-8478(24)00172-9. [Epub ahead of print] 100147
    Multiplexed multi-modal single cell technologies: From observation to perturbation analysis.
    Su-Hyeon Lee, Junha Park, Byungjin Hwang.
      Single cell technologies have undergone significant transformation, expanding from their initial focus on transcriptomics to encompass a diverse range of modalities. Recent advancements have markedly improved scalability and reduced costs, facilitating the processing of larger cell populations and broadening the scope of single cell research. The incorporation of CRISPR-based perturbations has revolutionized the field by enabling precise functional genomics and detailed studies of gene regulation at the single cell level. Despite these advancements, challenges persist, particularly in achieving genome-wide perturbations and managing the complexity of high-throughput data. This review discusses the technological milestones that have driven these changes, the current limitations of single cell CRISPR technologies, and the future directions needed to address these challenges and advance our understanding of cellular biology.
    Keywords:  CRISPR; Single cell sequencing; combinatorial indexing; multi-omics
    DOI:  https://doi.org/10.1016/j.mocell.2024.100147
  15. BMB Rep. 2024 Nov 11. pii: 6251. [Epub ahead of print]
    DNA regulatory element cooperation and competition in transcription.
    Haram Lee, Meyer Joseph Friedman, Sang Bum Kim, Soohwan Oh.
      Regulation of eukaryotic transcription is a complex process that enables precise temporal and spatial control of gene expression. Promoters, which are cis-regulatory elements (CREs) located proximal to the transcription start site (TSS), selectively integrate regulatory cues from distal CREs, or enhancers, and their associated transcriptional machinery. In this review, we discuss current knowledge regarding CRE cooperation and competition impacting gene expression, including features of enhancer-promoter, enhancer-enhancer, and promoter-promoter interplay. We also provide an overview of recent insights into the underlying molecular mechanisms that facilitate physical and functional interaction of regulatory elements, such as the involvement of enhancer RNAs and biomolecular condensates.
  16. Comput Biol Med. 2024 Nov 08. pii: S0010-4825(24)01407-0. [Epub ahead of print]184 109322
    Improving the identification of cancer driver modules using deep features learned from multi-omics data.
    Yang Guo, Lingling Liu, Aofeng Lin.
      Identifying the cancer driver modules or pathways is crucial to understanding the fundamental mechanisms of cancer occurrence and progression. The rapid abundance of cancer omics data provides unprecedented opportunities to study the driver modules in cancer, and many computational methods have been developed in recent years. However, most existing methods have limitations in considering different types of cancer omics data and cannot effectively learn informative omics features for integrated identification of driver modules. In this paper, we introduce a new integrated framework to accurately identify the cancer driver modules by integrating the protein-protein interaction network, transcriptional regulatory network, gene expression and mutation data in cancer. We first develop a series of methods to learn the deep features of functional connectivity between genes in each omics data and then construct an integrated gene functional coherence network. Furthermore, we present a two-step module mining method to efficiently identify the cancer driver modules from the integrated gene functional coherence network. Systematic experiments in three cancer types demonstrate that the proposed framework can obtain more significant driver modules than most existing methods, and some identified driver modules are associated with clinical survival phenotypes.
    Keywords:  Cancer driver modules; Deep features; Integrated gene network; Multi-omics data
    DOI:  https://doi.org/10.1016/j.compbiomed.2024.109322
  17. Cancers (Basel). 2024 Oct 30. pii: 3664. [Epub ahead of print]16(21):
    Ex Vivo Intestinal Organoid Models: Current State-of-the-Art and Challenges in Disease Modelling and Therapeutic Testing for Colorectal Cancer.
    Sarron Randall-Demllo, Ghanyah Al-Qadami, Anita E Raposo, Chenkai Ma, Ilka K Priebe, Maryam Hor, Rajvinder Singh, Kim Y C Fung.
      Despite improvements in participation in population-based screening programme, colorectal cancer remains a major cause of cancer-related mortality worldwide. Targeted interventions are desirable to reduce the health and economic burden of this disease. Two-dimensional monolayers of colorectal cancer cell lines represent the traditional in vitro models for disease and are often used for diverse purposes, including the delineation of molecular pathways associated with disease aetiology or the gauging of drug efficacy. The lack of complexity in such models, chiefly the limited epithelial cell diversity and differentiation, attenuated mucus production, lack of microbial interactions and mechanical stresses, has driven interest in the development of more holistic and physiologically relevant in vitro model systems. In particular, established ex vivo patient-derived explant and patient-derived tumour xenograft models have been supplemented by progress in organoid and microfluidic organ-on-a-chip cultures. Here, we discuss the applicability of advanced culturing technologies, such as organoid systems, as models for colorectal cancer and for testing chemotherapeutic drug sensitivity and efficacy. We highlight current challenges associated with organoid technologies and discuss their future for more accurate disease modelling and personalized medicine.
    Keywords:  3D culture; colorectal cancer; disease modelling; ex vivo models; intestinal organoid; organ-on-a-chip; therapeutic screening
    DOI:  https://doi.org/10.3390/cancers16213664
  18. Nat Cell Biol. 2024 Nov 15.
    Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration.
    Mardi Fink, Kizito Njah, Shyam J Patel, David P Cook, Vanessa Man, Francesco Ruso, Arsheen Rajan, Masahiro Narimatsu, Andreea Obersterescu, Melanie J Pye, Daniel Trcka, Kin Chan, Arshad Ayyaz, Jeffrey L Wrana.
      Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair.
    DOI:  https://doi.org/10.1038/s41556-024-01550-4
  19. Nat Methods. 2024 Nov;21(11): 1974
    Multi-pass nanopore for single-molecule protein sequencing.
    Arunima Singh.
      
    DOI:  https://doi.org/10.1038/s41592-024-02509-x
  20. Nature. 2024 Nov 13.
    Clinical functional proteomics of intercellular signalling in pancreatic cancer.
    Peiwu Huang, Weina Gao, Changying Fu, Min Wang, Yunguang Li, Bizhu Chu, An He, Yuan Li, Xiaomei Deng, Yehan Zhang, Qian Kong, Jingxiong Yuan, Hebin Wang, Yu Shi, Dong Gao, Renyi Qin, Tony Hunter, Ruijun Tian.
      Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis1. Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We applied TMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR-PTPN11-FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.
    DOI:  https://doi.org/10.1038/s41586-024-08225-y
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