More Like this

1. Working a second job: Cell adhesion proteins that moonlight in the nucleus

   https://doi.org/10.3389/fcell.2023.1163553  

   Haage, Amanda; Dhasarathy, Archana (April 2023, Frontiers in Cell and Developmental Biology)

   Cells are adept at sensing changes in their environment, transmitting signals internally to coordinate responses to external stimuli, and thereby influencing adaptive changes in cell states and behavior. Often, this response involves modulation of gene expression in the nucleus, which is seen largely as a physically separated process from the rest of the cell. Mechanosensing, whereby a cell senses physical stimuli, and integrates and converts these inputs into downstream responses including signaling cascades and gene regulatory changes, involves the participation of several macromolecular structures. Of note, the extracellular matrix (ECM) and its constituent macromolecules comprise an essential part of the cellular microenvironment, allowing cells to interact with each other, and providing both structural and biochemical stimuli sensed by adhesion transmembrane receptors. This highway of information between the ECM, cell adhesion proteins, and the cytoskeleton regulates cellular behavior, the disruption of which results in disease. Emerging evidence suggests a more direct role for some of these adhesion proteins in chromatin structure and gene regulation, RNA maturation and other non-canonical functions. While many of these discoveries were previously limited to observations of cytoplasmic-nuclear transport, recent advances in microscopy, and biochemical, proteomic and genomic technologies have begun to significantly enhance our understanding of the impact of nuclear localization of these proteins. This review will briefly cover known cell adhesion proteins that migrate to the nucleus, and their downstream functions. We will outline recent advances in this very exciting yet still emerging field, with impact ranging from basic biology to disease states like cancer. 

   more » « less
2. Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration

   https://doi.org/10.3389/fcell.2022.933042  

   Cai, Grace; Nguyen, Anh; Bashirzadeh, Yashar; Lin, Shan-Shan; Bi, Dapeng; Liu, Allen P. (October 2022, Frontiers in Cell and Developmental Biology)

   Cellular unjamming is the collective fluidization of cell motion and has been linked to many biological processes, including development, wound repair, and tumor growth. In tumor growth, the uncontrolled proliferation of cancer cells in a confined space generates mechanical compressive stress. However, because multiple cellular and molecular mechanisms may be operating simultaneously, the role of compressive stress in unjamming transitions during cancer progression remains unknown. Here, we investigate which mechanism dominates in a dense, mechanically stressed monolayer. We find that long-term mechanical compression triggers cell arrest in benign epithelial cells and enhances cancer cell migration in transitions correlated with cell shape, leading us to examine the contributions of cell–cell adhesion and substrate traction in unjamming transitions. We show that cadherin-mediated cell–cell adhesion regulates differential cellular responses to compressive stress and is an important driver of unjamming in stressed monolayers. Importantly, compressive stress does not induce the epithelial–mesenchymal transition in unjammed cells. Furthermore, traction force microscopy reveals the attenuation of traction stresses in compressed cells within the bulk monolayer regardless of cell type and motility. As traction within the bulk monolayer decreases with compressive pressure, cancer cells at the leading edge of the cell layer exhibit sustained traction under compression. Together, strengthened intercellular adhesion and attenuation of traction forces within the bulk cell sheet under compression lead to fluidization of the cell layer and may impact collective cell motion in tumor development and breast cancer progression. 

   more » « less
3. The Transcriptional Coregulatory Protein YAP1 Interacts with RNA Binding Protein NPM1

   Dwead, Abdulrahman; Al-Mathkour, Marwah; Cinar, Bekir (April 2022, Experimental Biology 2022 Annual Meeting)

   RNA binding proteins (RBPs) regulate all aspects of RNA biogenesis from transcription, splicing, and translation to degradation, and they have a critical role in cellular homeostasis and functional diversity. Recent studies have indicated that altered expressions of RBPs are associated with many human diseases ranging from neurologic disorders to cancer. The transcriptional coregulator yes-associated protein 1 (YAP1), a critical nuclear effector of the mammalian Hippo pathway, regulates cell fate, cell contact, metabolism, and developmental processes. This study demonstrates a link between YAP1 and nucleophosmin1 (NPM1) protein. NPM1 is an RNA-binding protein that regulates many cellular activities, including ribosome biogenesis, RNA processing, chromatin remodeling, DNA repair, and genomic stability. We identified NPM1 from YAP1 protein complexes of androgen-responsive human cancer cells using proteomics approaches. Our proximity ligation assay demonstrated that YAP1 and NPM1 physically interacted with each other. The interaction between YAP1 and NPM1 occurred in cell nuclei and was regulated by androgen hormone signaling. In addition, our GST-pulldown assay demonstrated that NPM1 formed a protein complex with the proline-rich domain of YAP1. Furthermore, our enhanced RNA interactome capture (eRIC) assay showed that androgen also regulated the interaction of RBPs to polyA+ mRNA within the cell. Consistent with this observation, our eRIC assay combined with the mass spectrometry method enabled us to identify distinct RBP patterns in human cancer cells that are genetically related but phenotypically different. These observations indicate that global alterations of RBPs under changing environmental conditions may have essential roles in cellular physiology and disease biology. 

   more » « less
4. Three-dimensional models of breast cancer–fibroblasts interactions

   https://doi.org/10.1177/1535370220917366  

   Singh, Sunil; Tran, Sydnie; Putman, Justin; Tavana, Hossein (May 2020, Experimental Biology and Medicine)

   Tumor microenvironment is a complex niche consisting of cancer cells and stromal cells in a network of extracellular matrix proteins and various soluble factors. Dynamic interactions among cellular and non-cellular components of the tumor microenvironment regulate tumor initiation and progression. Fibroblasts are the most abundant stromal cell type and dynamically interact with cancer cells both in primary tumors and in metastases. Cancer cells activate resident fibroblasts to produce and secrete soluble signaling molecules that support proliferation, migration, matrix invasion, and drug resistance of cancer cell and tumor angiogenesis. In recent years, various forms of three-dimensional tumor models have been developed to study tumor–stromal interactions and to identify anti-cancer drugs that block these interactions. There is currently a technological gap in development of tumor models that are physiologically relevant, scalable, and allow convenient, on-demand addition of desired components of the tumor microenvironment. In this review, we discuss three studies from our group that focus on developing bioengineered models to study tumor-stromal signaling. We will present these studies chronologically and based on their increasing complexity. We will discuss the validation of the models using a CXCL12-CXCR4 chemokine-receptor signaling present among activated fibroblasts and breast cancer cells in solid tumors, highlight the advantages and shortcomings of the models, and conclude with our perspectives on their applications. Impact statement Tumor stroma plays an important role in progression of cancers to a fatal metastatic disease. Modern treatment strategies are considering targeting tumor stroma to improve outcomes for cancer patients. A current challenge to develop stroma-targeting therapeutics is the lack of preclinical physiologic tumor models. Animal models widely used in cancer research lack human stroma and are not amenable to screening of chemical compounds for cancer drug discovery. In this review, we outline in vitro three-dimensional tumor models that we have developed to study the interactions among cancer cells and stromal cells. We describe development of the tumor models in a modular fashion, from a spheroid model to a sophisticated organotypic model, and discuss the importance of using correct physiologic models to recapitulate tumor-stromal signaling. These biomimetic tumor models will facilitate understanding of tumor-stromal signaling biology and provide a scalable approach for testing and discovery of cancer drugs. 

   more » « less
5. Clay calcination technology: state-of-the-art review by the RILEM TC 282-CCL

   https://doi.org/10.1617/s11527-021-01807-6  

   Hanein, Theodore; Thienel, Karl-Christian; Zunino, Franco; Marsh, Alastair T.; Maier, Matthias; Wang, Bin; Canut, Mariana; Juenger, Maria C.; Ben Haha, Mohsen; Avet, François; et al (January 2022, Materials and Structures)

   Abstract The use of calcined clays as supplementary cementitious materials provides the opportunity to significantly reduce the cement industry’s carbon burden; however, use at a global scale requires a deep understanding of the extraction and processing of the clays to be used, which will uncover routes to optimise their reactivity. This will enable increased usage of calcined clays as cement replacements, further improving the sustainability of concretes produced with them. Existing technologies can be adopted to produce calcined clays at an industrial scale in many regions around the world. This paper, produced by RILEM TC 282-CCL on calcined clays as supplementary cementitious materials (working group 2), focuses on the production of calcined clays, presents an overview of clay mining, and assesses the current state of the art in clay calcination technology, covering the most relevant aspects from the clay deposit to the factory gate. The energetics and associated carbon footprint of the calcination process are also discussed, and an outlook on clay calcination is presented, discussing the technological advancements required to fulfil future global demand for this material in sustainable infrastructure development. 

   more » « less