Treatment resistance leads to cancer patient mortality. Therapeutic approaches that employ synthetic lethality to target mutational vulnerabilities in key tumor cell signaling pathways have proven effective in overcoming therapeutic resistance in some cancers. Yet, tumors are organs composed of malignant cells residing within a cellular and noncellular stroma. Tumor evolution and resistance to anticancer treatment are mediated through a dynamic and reciprocal dialogue with the tumor microenvironment (TME). Accordingly, expanding tumor cell synthetic lethality to encompass contextual synthetic lethality has the potential to eradicate tumors by targeting critical TME circuits that promote tumor progression and therapeutic resistance. In this Review, we summarize current knowledge about the TME and discuss its role in treatment. We outline the concept of tumor cell–specific synthetic lethality and describe therapeutic approaches to expand this paradigm to leverage TME synthetic lethality to improve cancer therapy.
Kevin J. Metcalf, Alaa Alazzeh, Zena Werb, Valerie M. Weaver
Continued thinning of the atmospheric ozone, which protects the earth from damaging ultraviolet radiation (UVR), will result in elevated levels of UVR reaching the earth’s surface, leading to a drastic increase in the incidence of skin cancer. In addition to promoting carcinogenesis in skin cells, UVR is a potent extrinsic driver of age-related changes in the skin known as “photoaging.” We are in the preliminary stages of understanding of the role of intrinsic aging in melanoma, and the tumor-permissive effects of photoaging on the skin microenvironment remain largely unexplored. In this Review, we provide an overview of the impact of UVR on the skin microenvironment, addressing changes that converge or diverge with those observed in intrinsic aging. Intrinsic and extrinsic aging promote phenotypic changes to skin cell populations that alter fundamental processes such as melanogenesis, extracellular matrix deposition, inflammation, and immune response. Given the relevance of these processes in cancer, we discuss how photoaging might render the skin microenvironment permissive to melanoma progression.
Asurayya Worrede, Stephen M. Douglass, Ashani T. Weeraratna
Many solid cancers metastasize to the bone and bone marrow (BM). This process may occur even before the diagnosis of primary tumors, as evidenced by the discovery of disseminated tumor cells (DTCs) in patients without occult malignancies. The cellular fates and metastatic progression of DTCs are determined by complicated interactions between cancer cells and BM niches. Not surprisingly, these niches also play important roles in normal biology, including homeostasis and turnover of skeletal and hematopoiesis systems. In this Review, we summarize recent findings on functions of BM niches in bone metastasis (BoMet), particularly during the early stage of colonization. In light of the rich knowledge of hematopoiesis and osteogenesis, we highlight how DTCs may progress into overt BoMet by taking advantage of niche cells and their activities in tissue turnover, especially those related to immunomodulation and bone repair.
Aaron M. Muscarella, Sergio Aguirre, Xiaoxin Hao, Sarah M. Waldvogel, Xiang H.-F. Zhang
Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.
Javid Moslehi, Andrew H. Lichtman, Arlene H. Sharpe, Lorenzo Galluzzi, Richard N. Kitsis
Nearly 140 years after Robert Koch discovered Mycobacterium tuberculosis, tuberculosis (TB) remains a global threat and a deadly human pathogen. M. tuberculosis is notable for complex host-pathogen interactions that lead to poorly understood disease states ranging from latent infection to active disease. Additionally, multiple pathologies with a distinct local milieu (bacterial burden, antibiotic exposure, and host response) can coexist simultaneously within the same subject and change independently over time. Current tools cannot optimally measure these distinct pathologies or the spatiotemporal changes. Next-generation molecular imaging affords unparalleled opportunities to visualize infection by providing holistic, 3D spatial characterization and noninvasive, temporal monitoring within the same subject. This rapidly evolving technology could powerfully augment TB research by advancing fundamental knowledge and accelerating the development of novel diagnostics, biomarkers, and therapeutics.
Alvaro A. Ordonez, Elizabeth W. Tucker, Carolyn J. Anderson, Claire L. Carter, Shashank Ganatra, Deepak Kaushal, Igor Kramnik, Philana L. Lin, Cressida A. Madigan, Susana Mendez, Jianghong Rao, Rada M. Savic, David M. Tobin, Gerhard Walzl, Robert J. Wilkinson, Karen A. Lacourciere, Laura E. Via, Sanjay K. Jain
With the growing number of transgender and gender-nonbinary individuals who are becoming visible, it is clear that there is a need to develop a rigorous evidence base to inform care practice. Transgender health research is often limited to HIV/AIDS or mental health research and is typically subsumed in larger studies with general LGBTQ focus. Although the number of knowledgeable health care providers remains modest, the model for the medical approach to transgender health is shifting owing to growing social awareness and an appreciation of a biological component. Gender-affirming medicine facilitates aligning the body of the transgender person with the gender identity; typical treatment regimens include hormone therapy and/or surgical interventions. While broadly safe, hormone treatments require some monitoring for safety. Exogenous estrogens are associated with a dose-dependent increase in venous thromboembolic risk, and androgens stimulate erythropoiesis. The degree to which progressing gender-affirming hormone treatment changes cancer risk, cardiac heart disease risk, and/or bone health remains unknown. Guidelines referencing the potential exacerbation of cancer, heart disease, or other disease risk often rely on physiology models, because conclusive clinical data do not exist. Dedicated research infrastructure and funding are needed to address the knowledge gap in the field.
Joshua D. Safer
Severe insulin resistance syndromes are a heterogeneous group of rare disorders characterized by profound insulin resistance, substantial metabolic abnormalities, and a variety of clinical manifestations and complications. The etiology of these syndromes may be hereditary or acquired, due to defects in insulin potency and action, cellular responsiveness to insulin, and/or aberrations in adipose tissue function or development. Over the past decades, advances in medical technology, particularly in genomic technologies and genetic analyses, have provided insights into the underlying pathophysiological pathways and facilitated the more precise identification of several of these conditions. However, the exact cellular and molecular mechanisms of insulin resistance have not yet been fully elucidated for all syndromes. Moreover, in clinical practice, many of the syndromes are often misdiagnosed or underdiagnosed. The majority of these disorders associate with an increased risk of severe complications and mortality; thus, early identification and personalized clinical management are of the essence. This Review aims to categorize severe insulin resistance syndromes by disease process, including insulin receptor defects, signaling defects, and lipodystrophies. We also highlight several complex syndromes and emphasize the need to identify patients, investigate underlying disease mechanisms, and develop specific treatment regimens.
Angeliki M. Angelidi, Andreas Filippaios, Christos S. Mantzoros
The extrinsic and autonomic nervous system intricately controls the major functions of the gastrointestinal tract through the enteric nervous system; these include motor, secretory, sensory, storage, and excretory functions. Disorders of the nervous system affecting gastrointestinal tract function manifest primarily as abnormalities in motor (rather than secretory) functions. Common gastrointestinal symptoms in neurologic disorders include sialorrhea, dysphagia, gastroparesis, intestinal pseudo-obstruction, constipation, diarrhea, and fecal incontinence. Diseases of the entire neural axis ranging from the cerebral hemispheres to the peripheral autonomic nerves can result in gastrointestinal motility disorders. The most common neurologic diseases affecting gastrointestinal function are stroke, parkinsonism, multiple sclerosis, and diabetic neuropathy. Diagnosis involves identification of the neurologic disease and its distribution, and documentation of segmental gut dysfunction, typically using noninvasive imaging, transit measurements, or intraluminal measurements of pressure activity and coordination of motility. Apart from treatment of the underlying neurologic disease, management focuses on restoration of normal hydration and nutrition and pharmacologic treatment of the gut neuromuscular disorder.
The etiopathogenesis of systemic lupus erythematosus (SLE), a clinically heterogeneous multisystemic syndrome that derives its name from the initial characterization of facial lesions that resemble the bite of a wolf, is considered a complex, multifactorial interplay between underlying genetic susceptibility factors and the environment. Prominent pathogenic factors include the induction of aberrant cell death pathways coupled with defective cell death clearance mechanisms that promote excessive externalization of modified cellular and nuclear debris with subsequent loss of tolerance to a wide variety of autoantigens and innate and adaptive immune dysregulation. While abnormalities in adaptive immunity are well recognized and are key to the pathogenesis of SLE, recent findings have emphasized fundamental roles of the innate immune system in the initiation and propagation of autoimmunity and the development of organ damage in this disease. This Review focuses on recent discoveries regarding the role of components of the innate immune system, specifically neutrophils and interferons, in promoting various aspects of lupus pathogenesis, with potential implications for novel therapeutic strategies.
Sarthak Gupta, Mariana J. Kaplan
Humans have been infected with Mycobacterium tuberculosis (Mtb) for thousands of years. While tuberculosis (TB), one of the deadliest infectious diseases, is caused by uncontrolled Mtb infection, over 90% of presumed infected individuals remain asymptomatic and contain Mtb in a latent TB infection (LTBI) without ever developing disease, and some may clear the infection. A small number of heavily Mtb-exposed individuals appear to resist developing traditional LTBI. Because Mtb has mechanisms for intracellular survival and immune evasion, successful control involves all of the arms of the immune system. Here, we focus on immune responses to Mtb in humans and nonhuman primates and discuss new concepts and outline major knowledge gaps in our understanding of LTBI, ranging from the earliest events of exposure and infection to success or failure of Mtb control.
W. Henry Boom, Ulrich E. Schaible, Jacqueline M. Achkar
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