Glioblastoma (GBM) is the most belligerent and frequent brain tumor in adults. Research over the past two decades has provided increased knowledge of the genomic and molecular landscape of GBM and highlighted the presence of a high degree of inter- and intratumor heterogeneity within the neoplastic compartment. It is now appreciated that GBMs are composed of multiple distinct and impressionable neoplastic and non-neoplastic cell types that form the unique brain tumor microenvironment (TME). Non-neoplastic cells in the TME form reciprocal interactions with neoplastic cells to promote tumor growth and invasion, and together they influence the tumor response to standard-of-care therapies as well as emerging immunotherapies. One of the most prevalent non-neoplastic cell types in the GBM TME are myeloid cells, the most abundant of which are of hematopoietic origin, including monocytes/monocyte-derived macrophages. Less abundant, although still a notable presence, are neutrophils of hematopoietic origin and intrinsic brain-resident microglia. In this Review we focus on neutrophils and monocytes that infiltrate tumors from the blood circulation, their heterogeneity, and their interactions with neoplastic cells and other non-neoplastic cells in the TME. We conclude with an overview of challenges in targeting these cells and discuss avenues for therapeutic exploitation to improve the dismal outcomes of patients with GBM.
Dinorah Friedmann-Morvinski, Dolores Hambardzumyan
Glioblastoma (GBM) is the most aggressive tumor in the central nervous system and contains a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME that contribute to most GBM hallmarks, including immunosuppression. The understanding of TAMs in GBM has been limited by the lack of powerful tools to characterize them. However, recent progress on single-cell technologies offers an opportunity to precisely characterize TAMs at the single-cell level and identify new TAM subpopulations with specific tumor-modulatory functions in GBM. In this Review, we discuss TAM heterogeneity and plasticity in the TME and summarize current TAM-targeted therapeutic potential in GBM. We anticipate that the use of single-cell technologies followed by functional studies will accelerate the development of novel and effective TAM-targeted therapeutics for GBM patients.
Fatima Khan, Lizhi Pang, Madeline Dunterman, Maciej S. Lesniak, Amy B. Heimberger, Peiwen Chen
Most proteins destined for the extracellular space or various intracellular compartments must traverse the intracellular secretory pathway. The first step is the recruitment and transport of cargoes from the endoplasmic reticulum (ER) lumen to the Golgi apparatus by coat protein complex II (COPII), consisting of five core proteins. Additional ER transmembrane proteins that aid cargo recruitment are referred to as cargo receptors. Gene duplication events have resulted in multiple COPII paralogs present in the mammalian genome. Here, we review the functions of each COPII protein, human disorders associated with each paralog, and evidence for functional conservation between paralogs. We also provide a summary of current knowledge regarding two prototypical cargo receptors in mammals, LMAN1 and SURF4, and their roles in human health and disease.
Vi T. Tang, David Ginsburg
Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts to untangle the metabolic underpinnings of this disease to find novel therapeutic avenues for treatment. An emerging focus in this field is fatty acid (FA) metabolism, which is critical for numerous diverse biological processes involved in GBM pathogenesis. These processes can be classified into four broad fates: anabolism, catabolism, regulation of ferroptosis, and the generation of signaling molecules. Each fate provides a unique perspective by which we can inspect GBM biology and gives us a road map to understanding this complicated field. This Review discusses the basic, translational, and clinical insights into each of these fates to provide a contemporary understanding of FA biology in GBM. It is clear, based on the literature, that there are far more questions than answers in the field of FA metabolism in GBM, and substantial efforts should be made to untangle these complex processes in this intractable disease.
Jason Miska, Navdeep S. Chandel
Hematopoietic stem cells, regulated by their microenvironment (or “niche”), sustain the production of mature blood and immune cells. Leukemia cells remodel the microenvironment to enhance their survival, which is accompanied by the loss of support for normal hematopoiesis in hematologic malignancies. Extracellular vesicles (EVs) mediate intercellular communication in physiological and pathological conditions, and deciphering their functions in cell-cell interactions in the ecosystem can highlight potential therapeutic targets. In this Review, we illustrate the utility of EVs derived from various cell types, focusing on the biological molecules they contain and the behavioral alterations they can induce in recipient cells. We also discuss the potential for clinical application in hematologic malignancies, including EV-based therapeutic regimens, drug delivery via EVs, and the use of EVs (or their cargoes) as biomarkers.
Guohuan Sun, Quan Gu, Junke Zheng, Hui Cheng, Tao Cheng
Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.
William G. Kaelin Jr.
Over the course of a human lifespan, genome integrity erodes, leading to an increased abundance of several types of chromatin changes. The abundance of DNA lesions (chemical perturbations to nucleotides) increases with age, as does the number of genomic mutations and transcriptional disruptions caused by replication or transcription of those lesions, respectively. At the epigenetic level, precise DNA methylation patterns degrade, likely causing increasingly stochastic variations in gene expression. Similarly, the tight regulation of histone modifications begins to unravel. The genomic instability caused by these mechanisms allows transposon element reactivation and remobilization, further mutations, gene dysregulation, and cytoplasmic chromatin fragments. This cumulative genomic instability promotes cell signaling events that drive cell fate decisions and extracellular communications known to disrupt tissue homeostasis and regeneration. In this Review, we focus on age-related epigenetic changes and their interactions with age-related genomic changes that instigate these events.
Carolina Soto-Palma, Laura J. Niedernhofer, Christopher D. Faulk, Xiao Dong
Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues — adipose, muscle, and liver — as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.
Allyson K. Palmer, Michael D. Jensen
SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as “long COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype. Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology. Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.
Jasimuddin Ahamed, Jeffrey Laurence
Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.
Lei Zhang, Louise E. Pitcher, Matthew J. Yousefzadeh, Laura J. Niedernhofer, Paul D. Robbins, Yi Zhu
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