bims-ectoca 2023-08-13 papers

Int J Mol Sci. 2023 Aug 02. pii: 12347. [Epub ahead of print]24(15):

Tumor Cells Transmit Drug Resistance via Cisplatin-Induced Extracellular Vesicles.

Jian Wang, Qingqing Liu, Yuanxin Zhao, Jiaying Fu, Jing Su.

Cisplatin is a first-line clinical agent used for treating solid tumors. Cisplatin damages the DNA of tumor cells and induces the production of high levels of reactive oxygen species to achieve tumor killing. Tumor cells have evolved several ways to tolerate this damage. Extracellular vesicles (EVs) are an important mode of information transfer in tumor cells. EVs can be substantially activated under cisplatin treatment and mediate different responses of tumor cells under cisplatin treatment depending on their different cargoes. However, the mechanism of action of tumor-cell-derived EVs under cisplatin treatment and their potential cargoes are still unclear. This review considers recent advances in cisplatin-induced release of EVs from tumor cells, with the expectation of providing a new understanding of the mechanisms of cisplatin treatment and drug resistance, as well as strategies for the combined use of cisplatin and other drugs.

Keywords: cisplatin; drug resistance; extracellular vesicles; non-coding RNA; oxidative stress

DOI: https://doi.org/10.3390/ijms241512347

Int J Mol Sci. 2023 Aug 06. pii: 12491. [Epub ahead of print]24(15):

YAP at the Crossroads of Biomechanics and Drug Resistance in Human Cancer.

Miao Huang, Heyang Wang, Cole Mackey, Michael C Chung, Juan Guan, Guangrong Zheng, Arkaprava Roy, Mingyi Xie, Christopher Vulpe, Xin Tang.

Biomechanical forces are of fundamental importance in biology, diseases, and medicine. Mechanobiology is an emerging interdisciplinary field that studies how biological mechanisms are regulated by biomechanical forces and how physical principles can be leveraged to innovate new therapeutic strategies. This article reviews state-of-the-art mechanobiology knowledge about the yes-associated protein (YAP), a key mechanosensitive protein, and its roles in the development of drug resistance in human cancer. Specifically, the article discusses three topics: how YAP is mechanically regulated in living cells; the molecular mechanobiology mechanisms by which YAP, along with other functional pathways, influences drug resistance of cancer cells (particularly lung cancer cells); and finally, how the mechanical regulation of YAP can influence drug resistance and vice versa. By integrating these topics, we present a unified framework that has the potential to bring theoretical insights into the design of novel mechanomedicines and advance next-generation cancer therapies to suppress tumor progression and metastasis.

Keywords: CRISPR/Cas9 imaging; bioengineering; biomechanics; cancer; drug resistance; extracellular matrix (ECM); mechanobiology; mechanomedicine; yes-associated protein (YAP)

DOI: https://doi.org/10.3390/ijms241512491

Genes Dis. 2023 Nov;10(6): 2528-2539

Hippo-YAP/TAZ signaling in osteogenesis and macrophage polarization: Therapeutic implications in bone defect repair.

Haochen Wang, Hui Yu, Tianyu Huang, Bin Wang, Lin Xiang.

Bone defects caused by diseases or surgery are a common clinical problem. Researchers are devoted to finding biological mechanisms that accelerate bone defect repair, which is a complex and continuous process controlled by many factors. As members of transcriptional costimulatory molecules, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play an important regulatory role in osteogenesis, and they affect cell function by regulating the expression of osteogenic genes in osteogenesis-related cells. Macrophages are an important group of cells whose function is regulated by YAP/TAZ. Currently, the relationship between YAP/TAZ and macrophage polarization has attracted increasing attention. In bone tissue, YAP/TAZ can realize diverse osteogenic regulation by mediating macrophage polarization. Macrophages polarize into M1 and M2 phenotypes under different stimuli. M1 macrophages dominate the inflammatory response by releasing a number of inflammatory mediators in the early phase of bone defect repair, while massive aggregation of M2 macrophages is beneficial for inflammation resolution and tissue repair, as they secrete many anti-inflammatory and osteogenesis-related cytokines. The mechanism of YAP/TAZ-mediated macrophage polarization during osteogenesis warrants further study and it is likely to be a promising strategy for bone defect repair. In this article, we review the effect of Hippo-YAP/TAZ signaling and macrophage polarization on bone defect repair, and highlight the regulation of macrophage polarization by YAP/TAZ.

Keywords: Bone defect repair; Hippo-YAP/TAZ signaling; Inflammation; Macrophage polarization; Osteogenesis

DOI: https://doi.org/10.1016/j.gendis.2022.12.012

Cell Signal. 2023 Aug 05. pii: S0898-6568(23)00260-7. [Epub ahead of print] 110846

Ca2+ signaling and the hippo pathway: Intersections in cellular regulation.

Samar Sayedyahossein, Louise Thines, David B Sacks.

The Hippo signaling pathway is a master regulator of organ size and tissue homeostasis. Hippo integrates a broad range of cellular signals to regulate numerous processes, such as cell proliferation, differentiation, migration and mechanosensation. Ca2+ is a fundamental second messenger that modulates signaling cascades involved in diverse cellular functions, some of which are also regulated by the Hippo pathway. Studies published over the last five years indicate that Ca2+ can influence core Hippo pathway components. Nevertheless, comprehensive understanding of the crosstalk between Ca2+ signaling and the Hippo pathway, and possible mechanisms through which Ca2+ regulates Hippo, remain to be elucidated. In this review, we summarize the multiple intersections between Ca2+ and the Hippo pathway and address the biological consequences.

Keywords: Calcium; Calmodulin; Hippo; S100; Signaling; YAP

DOI: https://doi.org/10.1016/j.cellsig.2023.110846

Proc Natl Acad Sci U S A. 2023 08 15. 120(33): e2211855120

HP1-driven phase separation recapitulates the thermodynamics and kinetics of heterochromatin condensate formation.

Maxime M C Tortora, Lucy D Brennan, Gary Karpen, Daniel Jost.

The spatial segregation of pericentromeric heterochromatin (PCH) into distinct, membrane-less nuclear compartments involves the binding of Heterochromatin Protein 1 (HP1) to H3K9me2/3-rich genomic regions. While HP1 exhibits liquid-liquid phase separation properties in vitro, its mechanistic impact on the structure and dynamics of PCH condensate formation in vivo remains largely unresolved. Here, using a minimal theoretical framework, we systematically investigate the mutual coupling between self-interacting HP1-like molecules and the chromatin polymer. We reveal that the specific affinity of HP1 for H3K9me2/3 loci facilitates coacervation in nucleo and promotes the formation of stable PCH condensates at HP1 levels far below the concentration required to observe phase separation in purified protein assays in vitro. These heterotypic HP1-chromatin interactions give rise to a strong dependence of the nucleoplasmic HP1 density on HP1-H3K9me2/3 stoichiometry, consistent with the thermodynamics of multicomponent phase separation. The dynamical cross talk between HP1 and the viscoelastic chromatin scaffold also leads to anomalously slow equilibration kinetics, which strongly depend on the genomic distribution of H3K9me2/3 domains and result in the coexistence of multiple long-lived, microphase-separated PCH compartments. The morphology of these complex coacervates is further found to be governed by the dynamic establishment of the underlying H3K9me2/3 landscape, which may drive their increasingly abnormal, aspherical shapes during cell development. These findings compare favorably to 4D microscopy measurements of HP1 condensate formation in live Drosophila embryos and suggest a general quantitative model of PCH formation based on the interplay between HP1-based phase separation and chromatin polymer mechanics.

Keywords: 3D genomics; biophysics; heterochromatin; microscopy; phase separation

DOI: https://doi.org/10.1073/pnas.2211855120

Cell Death Dis. 2023 08 05. 14(8): 503

Heterogeneity in leukemia cells that escape drug-induced senescence-like state.

David Miller, Kyra Kerkhofs, Farnoosh Abbas-Aghababazadeh, Sahib Singh Madahar, Mark D Minden, Josée Hébert, Benjamin Haibe-Kains, Mark A Bayfield, Samuel Benchimol.

Erythropoietin (EPO) suppresses drug-induced apoptosis in EPO-receptor-positive leukemia cells and allows cells to persist after drug treatment by promoting cellular senescence. Importantly a small proportion of senescent cells can re-enter the cell cycle and resume proliferation after drug treatment, resulting in disease recurrence/persistence. Using a single-cell assay to track individual cells that exit a drug-induced senescence-like state, we show that cells exhibit asynchronous exit from a senescent-like state, and display different rates of proliferation. Escaped cells retain sensitivity to drug treatment, but display inter-clonal variability. We also find heterogeneity in gene expression with some of the escaped clones retaining senescence-associated gene expression. Senescent leukemia cells exhibit changes in gene expression that affect metabolism and senescence-associated secretory phenotype (SASP)-related genes. Herein, we generate a senescence gene signature and show that this signature is a prognostic marker of worse overall survival in AML and multiple other cancers. A portion of senescent leukemia cells depend on lysosome activity; chloroquine, an inhibitor of lysosome activity, promotes senolysis of some senescent leukemia cells. Our study indicates that the serious risks associated with the use of erythropoietin-stimulating agents (ESAs) in anemic cancer patients may be attributed to their ability to promote drug-tolerant cancer cells through the senescence program.

DOI: https://doi.org/10.1038/s41419-023-06015-4