Targeting FSP1 to induce ferroptosis in chromophobe renal cell carcinoma.

There are no proven therapies for metastatic or unresectable Chromophobe Renal Cell Carcinoma (ChRCC). ChRCC is characterized by high glutathione levels and hypersensitivity to ferroptosis, an iron-dependent form of cell death characterized by peroxidation of polyunsaturated fatty acids. The underlying mechanisms leading to ferroptosis hypersensitivity are unknown.

Prospects for ferroptosis therapies in cancer.

Ferroptosis is a nonapoptotic form of cell death characterized by lethal membrane lipid peroxidation. This mechanism was first characterized in cancer cells well over a decade ago, and there is much enthusiasm for the concept that certain cancers may be treated by inducing ferroptosis. However, therapies that engage ferroptosis have yet to enter clinical testing.

Lipidomics and metabolomics as potential biomarkers for breast cancer progression.

Breast cancer is the most prevalent cancer among women in the United States, representing ~30% of all new female cancer cases annually. For the year 2024, it is estimated that 310,720 new instances of invasive breast cancer will be diagnosed, and breast cancer will be responsible for over 42,000 deaths among women. Today, despite the availability of numerous treatments for breast cancer and its symptoms, most cancer-related deaths result from metastasis for which there is no treatment.

Activation of lysosomal iron triggers ferroptosis in cancer.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis; by contrast, small molecules can provide spatiotemporal control of the chemistry at work.

Hotspots of Escape: Oxidative Niches Prime Tumor Cell Dissemination.

The balance between reactive oxygen species (ROS) and antioxidant defenses plays a critical role in tumor development, progression, and response to therapy. However, the detection of ROS in vivo remains technically challenging. In a recent Nature Cell Biology publication, Ueda and colleagues developed a tool to help address this: T-AP1, a tumor-targeted probe that tracks extracellular H2O2 and allows for detection of ROS in vivo.

High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non-Small Cell Lung Cancer in Patients.

Intraoperative 13C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.

Deep imaging of LepR stromal cells in optically cleared murine bone hemisections.

Tissue clearing combined with high-resolution confocal imaging is a cutting-edge approach for dissecting the three-dimensional (3D) architecture of tissues and deciphering cellular spatial interactions under physiological and pathological conditions. Deciphering the spatial interaction of leptin receptor-expressing (LepR) stromal cells with other compartments in the bone marrow is crucial for a deeper understanding of the stem cell niche and the skeletal tissue. In this study, we introduce an optimized protocol for the 3D analysis of skeletal tissues, enabling the visualization of hematopoietic and stromal cells, especially LepR stromal cells, within optically cleared bone hemisections.

Lymphatic collection and cell isolation from mouse models for multiomic profiling.

Premetastatic cancer cells often spread from the primary lesion through the lymphatic vasculature and, clinically, the presence or absence of lymph node metastases impacts treatment decisions. However, little is known about cancer progression via the lymphatic system or of the effect that the lymphatic environment has on cancer progression. This is due, in part, to the technical challenge of studying lymphatic vessels and collecting lymph fluid.

Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice.

Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing.

Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.

Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a posttranslational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to affect metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homolog of SELENOO.

Lymphatic system regulation of anti-cancer immunity and metastasis.

Cancer dissemination to lymph nodes (LN) is associated with a worse prognosis, increased incidence of distant metastases and reduced response to therapy. The LN microenvironment puts selective pressure on cancer cells, creating cells that can survive in LN as well as providing survival advantages for distant metastatic spread. Additionally, the presence of cancer cells leads to an immunosuppressive LN microenvironment, favoring the evasion of anti-cancer immune surveillance.

Leptin receptor cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor.

The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this is regulated. Here we found that nerve growth factor (NGF) produced by leptin receptor-expressing (LepR) stromal cells is required to maintain nerve fibres in adult bone marrow. In nerveless bone marrow, steady-state haematopoiesis was normal but haematopoietic and vascular regeneration were impaired after myeloablation.

Cancer immunotherapy response persists after lymph node resection.

Lymphatic transport facilitates the presentation of cancer antigens in tumor-draining lymph nodes (tdLNs), leading to T cell activation and the generation of systemic antitumor immune surveillance. Surgical removal of LNs to control cancer progression is routine in clinical practice. However, whether removing tdLNs impairs immune checkpoint blockade (ICB) is still controversial.

Dynamic lipidome alterations associated with human health, disease and ageing.

Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.

Advancements in melanoma cancer metastasis models.

Metastatic melanoma is a complex and deadly disease. Due to its complexity, the development of novel therapeutic strategies to inhibit metastatic melanoma remains an outstanding challenge. Our ability to study metastasis is advanced with the development of in vitro and in vivo models that better mimic the different steps of the metastatic cascade beginning from primary tumor initiation to final metastatic seeding.

In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.

In mice and humans with cancer, intravenous C-glucose infusion results in C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD by the ETC. However, C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified.

Emerging metabolomic tools to study cancer metastasis.

Metastasis is responsible for 90% of deaths in patients with cancer. Understanding the role of metabolism during metastasis has been limited by the development of robust and sensitive technologies that capture metabolic processes in metastasizing cancer cells. We discuss the current technologies available to study (i) metabolism in primary and metastatic cancer cells and (ii) metabolic interactions between cancer cells and the tumor microenvironment (TME) at different stages of the metastatic cascade.

Redox Regulation in Cancer Cells during Metastasis.

Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance.

A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis.

Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors. LEPR cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin, distinguishes peri-arteriolar LEPR cells poised to undergo osteogenesis from peri-sinusoidal LEPR cells poised to undergo adipogenesis (but retaining osteogenic potential).

Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues.

Little is known about the metabolic regulation of rare cell populations because most metabolites are hard to detect in small numbers of cells. We previously described a method for metabolomic profiling of flow cytometrically isolated hematopoietic stem cells (HSCs) that detects 60 metabolites in 10,000 cells (Agathocleous et al., 2017).

Metabolic heterogeneity confers differences in melanoma metastatic potential.

Metastasis requires cancer cells to undergo metabolic changes that are poorly understood. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers.