L-type amino acid transporter 1 (LAT1; SLC7A5), which preferentially transports large neutral amino acids (LNAAs), is highly upregulated in various cancers and represents a promising therapeutic target. The first-in-class LAT1-specific inhibitor, nanvuranlat (JPH203, KYT-0353), has exhibited potent anti-cancer effects and is under clinical evaluation. However, alterations in the amino acid availability in cancer cells underlying its pharmacological activities remain to be elucidated.

The interplay between extracellular matrix (ECM) biophysical properties and nutrient availability is crucial in cancer metabolism, but the specific influence of different ECM components remains unclear. This study investigates how collagen and fibrin 3D hydrogels, with varying stiffness, alongside different glucose concentrations, differentially regulate the metabolic phenotype of A549 lung and Panc1 pancreatic cancer spheroids. We observed that while glucose availability predominantly dictates metabolic profiles in collagen-based matrices, particularly influencing A549 cell behavior, metabolic adaptation in fibrin hydrogels was co-regulated by matrix properties and glucose levels. Notably, lung cancer cells shifted towards glycolysis under high glucose in collagen, whereas pancreatic cancer cells, inherently more glycolytic, exhibited metabolic rigidity, especially under low glucose, irrespective of collagen stiffness. Conversely, fibrin matrices generally induced a less noticeable, more quiescent metabolic state in both cancer cells, particularly under glucose deprivation. Specifically, higher collagen concentrations tended to support anaerobic metabolism, especially under glucose scarcity. The findings of this study reveal a hierarchical interplay where ECM composition tunes the sensitivity of cancer cells to nutrient availability, underscoring the necessity of integrating both matrix-specific mechanical cues and nutrient gradients in advanced 3D tumor models for identifying context-dependent metabolic vulnerabilities. This could have potential implications for designing future effective therapeutic strategies targeting the tumor microenvironment.

Colorectal cancer (CRC) is a globally prevalent malignancy that poses a substantial threat to human health. Despite advancements in prevention, diagnosis, and treatment, CRC remains a formidable clinical challenge due to the incomplete elucidation of its pathological mechanisms. Glutamine, an abundant amino acid, exerts pivotal roles in energy production, redox homeostasis, macromolecular biosynthesis, and signal transduction within cancer cells. Elucidating the role of glutamine in CRC pathogenesis is therefore of profound significance. In this study, we investigated the regulatory role of Cyclin-dependent kinase 5 (Cdk5) in glutamine metabolism in CRC, employing both human CRC cell models and murine models. Our findings demonstrated that Cdk5 knockdown accelerated glutamine uptake while suppressing the proliferation of CRC cells. Further exploration of the underlying molecular mechanisms revealed that Cdk5 physically interacts with EZH2. Besides, Cdk5 phosphorylates EZH2 at specific sites, and then the PRC2 complex (centered around EZH2) catalyzes the production of H3K27me3, an inhibitory marker, to regulate the expression of genes involved in glutamine metabolism. At the same time, we also found that modulation of the Cdk5-EZH2 axis alters the epigenetic landscape of genes associated with glutamine transporters and tricarboxylic acid cycle (TCA) enzymes, resulting in reduced mitochondrial activity, impaired glutamine utilization in the TCA cycle, and decreased ATP production-collectively impacting the global glutamine metabolic processes in CRC cells. In in vivo experiments utilizing a murine CRC model, we established five experimental groups. Results showed that Dinaciclib treatment suppressed tumor growth in the CRC model, with this inhibitory effect being further potentiated upon combination with glutamine deprivation. These findings not only uncover the intricate interplay between Cdk5, EZH2, and glutamine metabolism in CRC but also offer novel insights into the pathogenic mechanisms of CRC and identify potential therapeutic targets.

Chemotherapy-induced peripheral neuropathy (CIPN) involves impaired microvascular neuronal perfusion and reduced bioenergetics. Compression and cryotherapy are potential preventive measures, yet their mechanism of acral temperature reduction remains unclear. This study aims to unravel the effects of pressure-adjusted static compression (PSC) on aerobic metabolic and endothelial responses in patients undergoing chemotherapy (CTX).

Colorectal cancer (CRC) is among the most prevalent malignant tumors, with liver metastasis as the leading cause of mortality. Although metabolic reprogramming is known to play a crucial role in tumor metastasis, our understanding of this process during colorectal cancer liver metastasis (CRLM) remains limited.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer with poor clinical outcomes. Malic enzyme 2 (ME2) is a mitochondrial enzyme that catalyzes the conversion of malate to pyruvate and has been proposed as a therapeutic target. ME2 is highly expressed in many cell types including TNBC cells. We sought to define the molecular and cellular consequences of ME2 inhibition to facilitate its clinical translation. Here, we systematically evaluated the cellular and molecular effects of ME2 knockdown (ME2kd) in multiple TNBC models. ME2kd had heterogeneous effects on proliferation, migration, and metabolic flexibility in TNBC cell lines. ME2kd MDA-MB-468 xenografts in nude mice grew significantly slower and conferred prolonged host survival. ME2kd caused distinct shifts in mitochondrial respiration and glycolysis, whereas metabolomic and transcriptomic analyses revealed altered tricarboxylic acid (TCA) cycle flux, glutamine consumption, and serine/glycine metabolism, partly through changes in malate-aspartate shuttle (MAS) activity. The interplay between ME2, the serine synthesis pathway and the MAS was investigated with metabolite deprivation and co-knockdown assays. Importantly, we determined the crystal structure of ME2 bound to the small-molecule inhibitor NPD-389 and identified the binding interactions that drive the inhibitory response. These findings help to clarify the role of ME2 in TNBC phenotypes and highlight the therapeutic potential of ME2 inhibition in precision oncology.

Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), are universally fatal pediatric brain tumors with no effective treatments. DIPG tumors actively utilize mitochondrial oxidative phosphorylation (OXPHOS). Inhibition of Complex I (a core OXPHOS component) by phenformin radiosensitizes DIPG in vitro and in vivo. However, phenformin’s clinical application is limited by its risk of lactic acidosis. We investigated whether co-administration of the pyruvate-dehydrogenase-kinase (PDK) inhibitor dichloroacetate (DCA) can mitigate phenformin-induced acidosis while enhancing its anti-tumor activity.

Lipid homeostasis is critical for pancreatic adenocarcinoma (PDAC) cell survival under hypoxic and nutrient-deprived conditions. Hypoxia inhibits unsaturated lipid biosynthesis, compelling cancer cells to depend on exogenous unsaturated lipids to counteract saturated lipid-induced toxicity. Our previous work revealed that cancer-associated fibroblasts (CAFs) secrete unsaturated lipids, primarily lysophosphatidylcholines (LPCs), to alleviate lipotoxic stress in PDAC cells. Here, we conducted a drug screen to identify compounds that bypass the rescue effect of exogenous LPCs on cancer cell survival under stress.

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology, and, while obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 and Py230 orthotopic models of obesity-accelerated BC growth in immune-competent mice, we investigated the role of systemic lipids on tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in individuals with obesity.

Cancer cells rely on serine biosynthesis for growth, but its regulation in colorectal cancer (CRC) remains not well understood. This study identifies the mC methyltransferase NSUN2 (NOP2/Sun domain family, member 2) as a key regulator of serine biosynthesis, revealing a novel mechanism driving CRC progression.

Human cells can synthesize methionine from homocysteine and folate-coupled methyl groups via the B-dependent enzyme methionine synthase (MTR). Yet, it has been known for decades that cancer cells fail to grow when methionine is replaced by homocysteine, a phenomenon known as methionine dependence. The underlying mechanism remains unknown.

Lipid accumulation is associated with breast cancer metastasis. However, the mechanisms underlying how breast cancer cells increase lipid stores and their functional role in disease progression remain incompletely understood. Herein we quantified changes in lipid metabolism and characterized cytoplasmic lipid droplets in metastatic versus non-metastatic breast cancer cells. C-labeled palmitate was used to determine differences in fatty acid (FA) uptake and oxidation. Despite similar levels of palmitate uptake, metastatic cells increase lipid accumulation and oxidation of endogenous FAs compared to non-metastatic cells. Isotope tracing also demonstrated that metastatic cells support increased de novo lipogenesis by converting higher levels of glutamine and glucose into the FA precursor, citrate. Consistent with this, metastatic cells displayed increased levels of fatty acid synthase (FASN) and de novo lipogenesis. Genetic depletion or pharmacologic inhibition of FASN reduced cell migration, survival in anoikis assays, and in vivo metastasis. Finally, global proteomic analysis indicated that proteins involved in proteasome function, mitotic cell cycle, and intracellular protein transport were reduced following FASN inhibition of metastatic cells. Overall, these studies demonstrate that breast cancer metastases accumulate FAs by increasingde novo lipogenesis, storing TAG as cytoplasmic lipid droplets, and catabolizing these stores to drive several FAO-dependent steps in metastasis.

Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited therapeutic options and poor survival outcomes. Therefore, the development of novel and selective anti-AML therapies is needed. 6-methoxydihydroavicine (6ME), a benzophenanthridine alkaloid, imparted selective AML cell death in vitro and in vivo. Mechanistically, 6ME inhibited fatty acid oxidation (FAO) by binding to and decreasing the activity of PPARδ, a transcription factor involved in FAO.

Despite decades of efforts to find successful treatment approaches, cachexia remains a major unmet medical need. This condition, that affects patients with diverse underlying conditions, is characterized by severe muscle loss and is associated with reduced quality of life and limited survival. Search for underlying mechanisms that may guide cachexia treatment has mainly evolved around potential atrophy-inducing roles of inflammatory mediators, and in cancer patients, tumor-derived factors. Recently, a new paradigm emerged as it is becoming evident that specific immune cells inhabit atrophic muscle tissue. Arginase 1 (Arg1) expression is characteristic of these immune cells. Studies of potential contributions of these immune cells to loss of muscle mass and function is in its infancy, and the contribution of ARG1 to these processes remains elusive.

Colon cancer is strongly influenced by lifestyle factors. Sociodemographic factors like sex and socioeconomic position (SEP) might modulate the relationship between lifestyle and colon cancer risk. Metabolomics offers potential to uncover biological mechanisms linking lifestyle and colon cancer.

Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells.

Cells adapt to nutrient fluctuations through both signaling and epigenetic mechanisms. While amino acid (AA) deprivation is known to suppress protein synthesis via mTORC1 inactivation, the epigenetic pathways that support cellular adaptation and recovery remain poorly understood. We investigated how chromatin and transcriptional changes contribute to maintaining translational capacity during AA restriction and priming cells for growth upon AA repletion.

Obesity exacerbates the severity of cervical intraepithelial neoplasia (CIN), potentially through metabolic alterations. This study investigates how the Kisspeptin/GPR54 signaling pathway mediates mitochondrial energy metabolism in obesity-related CIN.

Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations represents a distinct subtype of leukemia. Emerging evidence suggests that regulation of redox metabolism contributes to tumorigenesis and reveals a metabolic vulnerability in anti-tumor therapies. However, the role of redox homeostasis between reactive oxygen species (ROS) and antioxidant systems plays in NPM1-mutated AML has not been fully elucidated.

Cancer cells exhibit abnormal dependence on glutamine, which is associated with the hyperactivation of γ-aminobutyric acid (GABA) metabolic pathways that promotes tumor growth. The α2-adrenergic receptor agonist dexmedetomidine (DEX) has been reported to promote colorectal cancers (CRC) progression. However, the role of GABAergic signaling in DEX-induced tumorigenesis remains unclear.