Cold Spring Harbor Perspectives in Medicine

Spatial findings have shaped on our understanding of breast cancer. In this review, we discuss how spatial methods, including spatial transcriptomics and proteomics and the resultant understanding of spatial relationships, have contributed to concepts regarding cancer progression and treatment. In addition to discussing traditional approaches, we examine how emerging multiplex imaging technologies have contributed to the field and how they might influence future research.

During the last decade, biomedical research has experienced a resurgence in the use of three-dimensional culture models for studies of normal and cancer biology. This resurgence has been driven by the development of models in which primary cells are grown in tissue-mimicking media and extracellular matrices to create organoid or organotypic cultures that more faithfully replicate the complex architecture and physiology of normal tissues and tumors. In addition, patient-derived tumor organoids preserve the three-dimensional organization and characteristics of the patient tumors ex vivo, becoming excellent preclinical models to supplement studies of tumor xenografts transplanted into immunocompromised mice...

Aging can be conceptualized as the progressive disequilibrium between stochastic damage accumulation and resilience mechanisms that continuously repair that damage, which eventually cause the development of chronic disease, frailty, and death. The immune system is at the forefront of these resilience mechanisms. Indeed, aging is associated with persistent activation of the immune system, witnessed by a high circulating level of inflammatory markers and activation of immune cells in the circulation and in tissue, a condition called "inflammaging...

In 2016, a group of researchers engaged in the development of patient-derived xenografts (PDXs) of human breast cancer provided a comprehensive review of the state of the field. In that review, they summarized the clinical problem that PDXs might address, the technical approaches to their generation (including a discussion of host animals and transplant conditions tested), and presented transplantation success (take) rates across groups and across transplantation conditions. At the time, there were just over 500 unique PDX models created by these investigators representing all three clinically defined subtypes (ER+ , HER2+ , and TNBC)...

The transition from a single, initiated cell to a full-blown malignant tumor involves significant genomic evolution. Exposure to carcinogens-whether directly mutagenic or not-can drive progression toward malignancy, as can stochastic acquisition of cancer-promoting genetic events. Mouse models using both carcinogens and germline genetic manipulations have enabled precise inquiry into the evolutionary dynamics that take place as a tumor progresses from benign to malignant to metastatic stages. Tumor progression is characterized by changes in somatic point mutations and copy-number alterations, even though any single tumor can itself have a high or low burden of genomic alterations...

Cells require micronutrients for numerous basic functions. Among these, iron, copper, and selenium are particularly critical for redox metabolism, and their importance is heightened during oncogene-driven perturbations in cancer. In this review, which particularly focuses on iron, we describe how these micronutrients are carefully chaperoned about the body and made available to tissues, a process that is designed to limit the toxicity of free iron and copper or by-products of selenium metabolism. We delineate perturbations in iron metabolism and iron-dependent proteins that are observed in cancer, and describe the current approaches being used to target iron metabolism and iron-dependent processes...

Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors...

NAD+ , the essential metabolite involved in multiple reactions such as the regulation of cellular metabolism, energy production, DNA repair, mitophagy and autophagy, inflammation, and neuronal function, has been the subject of intense research in the field of aging and disease over the last decade. NAD+ levels decline with aging and in some age-related diseases, and reduction in NAD+ affects all the hallmarks of aging. Here, we present an overview of the discovery of NAD+ , the cellular pathways of producing and consuming NAD+ , and discuss how imbalances in the production rate and cellular request of NAD+ likely contribute to aging and age-related diseases including neurodegeneration...

Rodent models of retinal degeneration are essential for the development of therapeutic strategies. In addition to living animal models, we here also discuss models based on rodent cell cultures, such as purified retinal ganglion cells and retinal explants. These ex vivo models extend the possibilities for investigating pathological mechanisms and assessing the neuroprotective effect of pharmacological agents by eliminating questions on drug pharmacokinetics and bioavailability. The number of living rodent models has greatly increased with the possibilities to achieve transgenic modifications in animals for knocking in and out genes and mutations...

Inherited retinal diseases (IRDs) are the leading cause of blindness in working-age individuals worldwide. Their genetic etiology is especially heterogenous, so the development of gene-specific therapies is unlikely to meet the medical needs of the entire patient community. Considering these challenges, a complementary strategy could be to develop therapies independent of the underlying gene variant causing retinal degeneration. As the retina is a neural tissue, it is in theory amenable to neuroprotective therapies that could help prolong cell survival or promote retinal function...

Molecular oxygen (O2 ) is essential for cellular bioenergetics and numerous biochemical reactions necessary for life. Solid tumors outgrow the native blood supply and diffusion limits of O2 , and therefore must engage hypoxia response pathways that evolved to withstand acute periods of low O2 Hypoxia activates coordinated gene expression programs, primarily through hypoxia inducible factors (HIFs), to support survival. Many of these changes involve metabolic rewiring such as increasing glycolysis to support ATP generation while suppressing mitochondrial metabolism...

Animal models, particularly genetically engineered mouse models (GEMMs), continue to have a transformative impact on our understanding of the initiation and progression of hematological malignancies and solid tumors. Furthermore, GEMMs have been employed in the design and optimization of potent anticancer therapies. Increasingly, drug responses are assessed in mouse models either prior, or in parallel, to the implementation of precision medical oncology, in which groups of patients with genetically stratified cancers are treated with drugs that target the relevant oncoprotein such that mechanisms of drug sensitivity or resistance may be identified...

Changes in mitochondrial function play a critical role in the basic biology of aging and age-related disease. Mitochondria are typically thought of in the context of ATP production and oxidant production. However, it is clear that the mitochondria sit at a nexus of cell signaling where they affect metabolite, redox, and energy status, which influence many factors that contribute to the biology of aging, including stress responses, proteostasis, epigenetics, and inflammation. This has led to growing interest in identifying mitochondrial targeted interventions to delay or reverse age-related decline in function and promote healthy aging...

This is a brief history of the work by many investigators throughout the world to find genes and mutations causing inherited retinal diseases (IRDs). It largely covers 40 years, from the late-1980s through today. Perhaps the best reason to study history is to better understand the present. The "present" for IRDs is exceptionally complex. Mutations in hundreds of genes are known to cause IRDs; tens of thousands of disease-causing mutations have been reported; clinical consequences are highly variable, even within the same family; and genetic testing, counseling, and clinical care are highly advanced but technically challenging...

In the last decade, organoid technology has become a cornerstone in cancer research. Organoids are long-term primary cell cultures, usually of epithelial origin, grown in a three-dimensional (3D) protein matrix and a fully defined medium. Organoids can be derived from many organs and cancer types and sites, encompassing both murine and human tissues. Importantly, they can be established from various stages during tumor evolution and recapitulate with high accuracy patient genomics and phenotypes in vitro, offering a platform for personalized medicine...

Optogenetics has emerged over the past 20 years as a powerful tool to investigate the various circuits underlying numerous functions, especially in neuroscience. The ability to control by light the activity of neurons has enabled the development of therapeutic strategies aimed at restoring some level of vision in blinding retinal conditions. Promising preclinical and initial clinical data support such expectations. Numerous challenges remain to be tackled (e.g., confirmation of safety, cell and circuit specificity, patterns, intensity and mode of stimulation, rehabilitation programs) on the path toward useful vision restoration...

Cellular senescence was initially described in the early 1960s by Hayflick and Moorehead. They noted sustained cell-cycle arrest after repeated subculturing of human primary cells. Over half a century later, cellular senescence has become recognized as one of the fundamental pillars of aging. Developing senotherapeutics, interventions that selectively eliminate or target senescent cells, has emerged as a key focus in health research. In this article, we note major milestones in cellular senescence research, discuss current challenges, and point to future directions for this rapidly growing field...

The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors...

The use of patient-derived xenografts (PDXs) has dramatically improved drug development programs. PDXs (1) reproduce the pathological features and the genomic profile of the parental tumors more precisely than other preclinical models, and (2) more faithfully predict therapy response. However, PDXs have limitations. These include the inability to completely capture tumor heterogeneity and the role of the immune system, the low engraftment efficiency of certain tumor types, and the consequences of the human-host interactions...

With the rapid expansion of methods encompassed by the term gene therapy, new trials exploring the safety and efficacy of these methods are initiated more frequently. As a result, important questions arise pertaining the design of these trials and patient participation. One of the most important aspects of any clinical trial is the ability to measure the trial's outcome in a manner that will reflect the effect of the treatment and allow its quantification, whether the trial is aimed at preservation or restoration of retinal cells (photoreceptors and others), vision, or both...