bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024‒10‒20
nine papers selected by
Xiao Qin, University of Oxford
  1. Scalable identification of lineage-specific gene regulatory networks from metacells with NetID.
  2. Data-driven batch detection enhances single-cell omics data analysis.
  3. What we need in colorectal cancer research, and why?
  4. Base editing screens define the genetic landscape of cancer drug resistance mechanisms.
  5. AAV-mediated gene therapies by miniature gene editing tools.
  6. Nongenetic evolution of the tumor: from challenges to new therapeutic opportunities.
  7. Epigenomic heterogeneity as a source of tumour evolution.
  8. Modeling lung adenocarcinoma metastases using patient-derived organoids.
  9. Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations.
  1. Genome Biol. 2024 Oct 18. 25(1): 275
    Scalable identification of lineage-specific gene regulatory networks from metacells with NetID.
    Weixu Wang, Yichen Wang, Ruiqi Lyu, Dominic Grün.
      The identification of gene regulatory networks (GRNs) is crucial for understanding cellular differentiation. Single-cell RNA sequencing data encode gene-level covariations at high resolution, yet data sparsity and high dimensionality hamper accurate and scalable GRN reconstruction. To overcome these challenges, we introduce NetID leveraging homogenous metacells while avoiding spurious gene-gene correlations. Benchmarking demonstrates superior performance of NetID compared to imputation-based methods. By incorporating cell fate probability information, NetID facilitates the prediction of lineage-specific GRNs and recovers known network motifs governing bone marrow hematopoiesis, making it a powerful toolkit for deciphering gene regulatory control of cellular differentiation from large-scale single-cell transcriptome data.
    DOI:  https://doi.org/10.1186/s13059-024-03418-0
  2. Cell Syst. 2024 Oct 16. pii: S2405-4712(24)00275-8. [Epub ahead of print]15(10): 893-894
    Data-driven batch detection enhances single-cell omics data analysis.
    Ziqi Zhang, Xiuwei Zhang.
      In single-cell omics studies, data are typically collected across multiple batches, resulting in batch effects: technical confounders that introduce noise and distort data distribution. Correcting these effects is challenging due to their unknown sources, nonlinear distortions, and the difficulty of accurately assigning data to batches that are optimal for integration methods.
    DOI:  https://doi.org/10.1016/j.cels.2024.09.011
  3. Adv Genet. 2024 ;pii: S0065-2660(24)00022-1. [Epub ahead of print]112 1-29
    What we need in colorectal cancer research, and why?
    Iker Badiola.
      Cancer is a complex disease that includes tumour and healthy cells surrounding and infiltrating the tumour. During cancer development, tumour cells release many extracellular signals in an autocrine and paracrine way, producing deep phenotypic changes in the surrounding cells, becoming protumoral actors. The entire entity composed of tumour cells and the recruited elements is known as the tumour microenvironment. Immune cells, fibroblasts and endothelial cells, mainly with the extracellular matrix, are the most common elements in different cancer types and coexist in a complex balance of protumoral and antitumoral factors. In this context, the spatial disposition of the tumour microenvironment elements is crucial to knowing the role of each one in the disease development, and the multiplex spatial technology is the way to map the tumours. The combination of spatial study with transcriptomic, proteomic, and epigenomic studies is the most modern tool in the hands of cancer researchers, and it has opened a new era in the study of cancer biology.
    Keywords:  Cancer biology; Cancer research; Colorectal cancer; Microenvironment
    DOI:  https://doi.org/10.1016/bs.adgen.2024.08.001
  4. Nat Genet. 2024 Oct 18.
    Base editing screens define the genetic landscape of cancer drug resistance mechanisms.
    Matthew A Coelho, Magdalena E Strauss, Alex Watterson, Sarah Cooper, Shriram Bhosle, Giuditta Illuzzi, Emre Karakoc, Cansu Dinçer, Sara F Vieira, Mamta Sharma, Marie Moullet, Daniela Conticelli, Jonas Koeppel, Katrina McCarten, Chiara M Cattaneo, Vivien Veninga, Gabriele Picco, Leopold Parts, Josep V Forment, Emile E Voest, John C Marioni, Andrew Bassett, Mathew J Garnett.
      Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes. We identify four functional classes of protein variants modulating drug sensitivity and use single-cell transcriptomics to reveal how these variants operate through distinct mechanisms, including eliciting a drug-addicted cell state. We identify variants that can be targeted with alternative inhibitors to overcome resistance and functionally validate an epidermal growth factor receptor (EGFR) variant that sensitizes lung cancer cells to EGFR inhibitors. Our variant-to-function map has implications for patient stratification, therapy combinations and drug scheduling in cancer treatment.
    DOI:  https://doi.org/10.1038/s41588-024-01948-8
  5. Sci China Life Sci. 2024 Sep 27.
    AAV-mediated gene therapies by miniature gene editing tools.
    Xiangfeng Kong, Tong Li, Hui Yang.
      The advent of CRISPR-Cas has revolutionized precise gene editing. While pioneering CRISPR nucleases like Cas9 and Cas12 generate targeted DNA double-strand breaks (DSB) for knockout or homology-directed repair, next generation CRISPR technologies enable gene editing without DNA DSB. Base editors directly convert bases, prime editors make diverse alterations, and dead Cas-regulator fusions allow nuanced control of gene expression, avoiding potentially risks like translocations. Meanwhile, the discovery of diminutive Cas12 orthologs and Obligate Mobile Element-Guided Activity (OMEGA) nucleases has overcome cargo limitations of adeno-associated viral vectors, expanding prospects for in vivo therapeutic delivery. Here, we review the ever-evolving landscape of cutting-edge gene editing tools, focusing on miniature Cas12 orthologs and OMEGA effectors amenable to single AAV packaging. We also summarize CRISPR therapies delivered using AAV vectors, discuss challenges such as efficiency and specificity, and look to the future of this transformative field of in vivo gene editing enabled by AAV vectors delivery.
    Keywords:  Obligate Mobile Element-Guided Activity (OMEGA); adeno-associated viruses (AAVs); gene therapy; genome editing; miniature CRISPR-Cas
    DOI:  https://doi.org/10.1007/s11427-023-2608-5
  6. Mol Oncol. 2024 Oct 18.
    Nongenetic evolution of the tumor: from challenges to new therapeutic opportunities.
    Elisa Oricchio.
      The ability of cancer cells to change and adapt poses a critical challenge to identifying curative solutions. Tumor evolution has been extensively studied from a genetic perspective, to guide clinicians in selecting the most appropriate therapeutic option based on a patient's mutational profile. However, several studies reported that tumors can evolve toward more aggressive stages or become resistant to therapies without changing their genetic makeup. Indeed, several cell-intrinsic and cell-extrinsic mechanisms contribute to tumor evolution. In this viewpoint, I focus on how chromatin, epigenetic, and transcriptional changes contribute to tumor evolution, allowing cancer cells to transition to different cell states and bypass response to therapies. Although tumor nongenetic evolution is harder to trace and predict, understanding its principles might open new therapeutic opportunities.
    Keywords:  chromatin; epigenetics; evolution; heterogeneity; transcription
    DOI:  https://doi.org/10.1002/1878-0261.13753
  7. Nat Rev Cancer. 2024 Oct 16.
    Epigenomic heterogeneity as a source of tumour evolution.
    Marthe Laisné, Mathieu Lupien, Céline Vallot.
      In the past decade, remarkable progress in cancer medicine has been achieved by the development of treatments that target DNA sequence variants. However, a purely genetic approach to treatment selection is hampered by the fact that diverse cell states can emerge from the same genotype. In multicellular organisms, cell-state heterogeneity is driven by epigenetic processes that regulate DNA-based functions such as transcription; disruption of these processes is a hallmark of cancer that enables the emergence of defective cell states. Advances in single-cell technologies have unlocked our ability to quantify the epigenomic heterogeneity of tumours and understand its mechanisms, thereby transforming our appreciation of how epigenomic changes drive cancer evolution. This Review explores the idea that epigenomic heterogeneity and plasticity act as a reservoir of cell states and therefore as a source of tumour evolution. Best practices to quantify epigenomic heterogeneity and explore its various causes and consequences are discussed, including epigenomic reprogramming, stochastic changes and lasting memory. The design of new therapeutic approaches to restrict epigenomic heterogeneity, with the long-term objective of limiting cancer development and progression, is also addressed.
    DOI:  https://doi.org/10.1038/s41568-024-00757-9
  8. Cell Rep Med. 2024 Oct 15. pii: S2666-3791(24)00522-6. [Epub ahead of print]5(10): 101777
    Modeling lung adenocarcinoma metastases using patient-derived organoids.
    Yuan Liu, Manendra Lankadasari, Joel Rosiene, Kofi E Johnson, Juan Zhou, Samhita Bapat, Lai-Fong L Chow-Tsang, Huasong Tian, Brooke Mastrogiacomo, Di He, James G Connolly, Harry B Lengel, Raul Caso, Elizabeth G Dunne, Cameron N Fick, Gaetano Rocco, Smita Sihag, James M Isbell, Mathew J Bott, Bob T Li, Piro Lito, Cameron W Brennan, Mark H Bilsky, Natasha Rekhtman, Prasad S Adusumilli, Marty W Mayo, Marcin Imielinski, David R Jones.
      Approximately 50% of patients with surgically resected early-stage lung cancer develop distant metastasis. At present, there is no in vivo metastasis model to investigate the biology of human lung cancer metastases. Using well-characterized lung adenocarcinoma (LUAD) patient-derived organoids (PDOs), we establish an in vivo metastasis model that preserves the biologic features of human metastases. Results of whole-genome and RNA sequencing establish that our in vivo PDO metastasis model can be used to study clonality and tumor evolution and to identify biomarkers related to organotropism. Investigation of the response of KRASG12C PDOs to sotorasib demonstrates that the model can examine the efficacy of treatments to suppress metastasis and identify mechanisms of drug resistance. Finally, our PDO model cocultured with autologous peripheral blood mononuclear cells can potentially be used to determine the optimal immune-priming strategy for individual patients with LUAD.
    Keywords:  coculture; drug resistance; immune priming; in vivo LUAD metastasis; lung adenocarcinoma; metastasis marker; patient-derived organoids; tumor evolution
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101777
  9. Nat Cancer. 2024 Oct 16.
    Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations.
    Khalil Kass Youssef, Nitin Narwade, Aida Arcas, Angel Marquez-Galera, Raúl Jiménez-Castaño, Cristina Lopez-Blau, Hassan Fazilaty, David García-Gutierrez, Amparo Cano, Joan Galcerán, Gema Moreno-Bueno, Jose P Lopez-Atalaya, M Angela Nieto.
      Epithelial-to-mesenchymal transition (EMT) triggers cell plasticity in embryonic development, adult injured tissues and cancer. Combining the analysis of EMT in cell lines, embryonic neural crest and mouse models of renal fibrosis and breast cancer, we find that there is not a cancer-specific EMT program. Instead, cancer cells dedifferentiate and bifurcate into two distinct and segregated cellular trajectories after activating either embryonic-like or adult-like EMTs to drive dissemination or inflammation, respectively. We show that SNAIL1 acts as a pioneer factor in both EMT trajectories, and PRRX1 drives the progression of the embryonic-like invasive trajectory. We also find that the two trajectories are plastic and interdependent, as the abrogation of the EMT invasive trajectory by deleting Prrx1 not only prevents metastasis but also enhances inflammation, increasing the recruitment of antitumor macrophages. Our data unveil an additional role for EMT in orchestrating intratumor heterogeneity, driving the distribution of functions associated with either inflammation or metastatic dissemination.
    DOI:  https://doi.org/10.1038/s43018-024-00839-5
This page is being maintained by Thomas Krichel. It was last updated on 2024‒10‒20 at 12:38.