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.
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
The discovery of microRNAs and their role in diseases was a breakthrough that inspired research into microRNAs as drug targets. Cardiovascular diseases are an area in which limitations of conventional pharmacotherapy are highly apparent and where microRNA-based drugs have appreciably progressed into preclinical and clinical testing. In this Review, we summarize the current state of microRNAs as therapeutic targets in the cardiovascular system. We report recent advances in the identification and characterization of microRNAs, their manipulation and clinical translation, and discuss challenges and perspectives toward clinical application.
Bernhard Laggerbauer, Stefan Engelhardt
Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
Elizabeth E. Wicks, Gregg L. Semenza
Cardiovascular disease (CVD) accounts for almost half of all deaths related to non-communicable disease worldwide, making it the single largest global cause of mortality. Although the risk factors for coronary artery disease — the most common cause of CVD — are well known and include hypertension, high cholesterol, age, and genetics, CVDs are now recognized as chronic inflammatory conditions. Arterial blockages, known as atherosclerosis, develop due to excess cholesterol accumulating within the arterial wall, creating a perpetually inflammatory state. The normally quiescent intimal layer of the vessel wall becomes laden with inflammatory cells, which alters the surrounding endothelial, smooth muscle, and extracellular matrix components to propagate disease. Macrophages, which can be either tissue resident or monocyte derived, are a key player in atherosclerotic disease progression and regression, and the understanding of their functions and origins continues to evolve with the use of deep phenotyping methodologies. This Review outlines how macrophages interact with each layer of the developing atherosclerotic plaque and discusses new concepts that are challenging our previous views on how macrophages function and our evolving understanding of the contribution of macrophages to disease.
Leah I. Susser, Katey J. Rayner
Autosomal dominant disorders present unique challenges, as therapeutics must often distinguish between healthy and diseased alleles while maintaining high efficiency, specificity, and safety. For this task, CRISPR/Cas remains particularly promising. Various CRISPR/Cas systems, like homology-directed repair, base editors, and prime editors, have been demonstrated to selectively edit mutant alleles either by incorporating these mutations into sgRNA sequences (near the protospacer-adjacent motif [“near the PAM”]) or by targeting a novel PAM generated by the mutation (“in the PAM”). However, these probability-based designs are not always assured, necessitating generalized, mutation-agnostic strategies like ablate-and-replace and single-nucleotide polymorphism editing. Here, we detail recent advancements in CRISPR therapeutics to treat a wide range of autosomal dominant disorders and discuss how they are altering the landscape for future therapies.
Salvatore Marco Caruso, Peter M.J. Quinn, Bruna Lopes da Costa, Stephen H. Tsang
The COVID-19 pandemic has elevated mRNA vaccines to global recognition due to their unprecedented success rate in protecting against a deadly virus. This international success is underscored by the remarkable versatility, favorable immunogenicity, and overall safety of the mRNA platform in diverse populations. Although mRNA vaccines have been studied in preclinical models and patients with cancer for almost three decades, development has been slow. The recent technological advances responsible for the COVID-19 vaccines have potential implications for successfully adapting this vaccine platform for cancer therapeutics. Here we discuss the lessons learned along with the chemical, biologic, and immunologic adaptations needed to optimize mRNA technology to successfully treat cancers.
Amanda L. Huff, Elizabeth M. Jaffee, Neeha Zaidi
Natural killer (NK) cells are innate immune cells that are critical to the body’s antitumor and antimetastatic defense. As such, novel therapies are being developed to utilize NK cells as part of a next generation of immunotherapies to treat patients with metastatic disease. Therefore, it is essential for us to examine how metastatic cancer cells and NK cells interact with each other throughout the metastatic cascade. In this Review, we highlight the recent body of work that has begun to answer these questions. We explore how the unique biology of cancer cells at each stage of metastasis alters fundamental NK cell biology, including how cancer cells can evade immunosurveillance and co-opt NK cells into cells that promote metastasis. We also discuss the translational potential of this knowledge.
Isaac S. Chan, Andrew J. Ewald
The gut microbiome is at the center of inflammatory bowel disease (IBD) pathogenesis and disease activity. While this has mainly been studied in the context of the bacterial microbiome, recent advances have provided tools for the study of host genetics and metagenomics of host-fungal interaction. Through these tools, strong evidence has emerged linking certain fungal taxa, such as Candida and Malassezia, with cellular and molecular pathways of IBD disease biology. Mouse models and human fecal microbial transplant also suggest that some disease-participatory bacteria and fungi may act not via the host directly, but via their fungal-bacterial ecologic interactions. We hope that these insights, and the study design and multi-omics strategies used to develop them, will facilitate the inclusion of the fungal community in basic and translational IBD research.
David M. Underhill, Jonathan Braun
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