Metabolic Alterations In Cancer Cells Research Articles

Porous Organic Polymer-Based Nanocomposites for Hypoxia Relieving and Enhanced Chemotherapy in Hepatocellular Carcinoma.

Uncontrolled proliferation and altered metabolism of cancer cells result in an imbalance of nutrients and oxygen supply, and persuade hypoxia. Hypoxia, in turn, activates the transcription gene HIF-1α, which eventually upregulates the efflux transporter P-gp and induces multidrug resistance (MDR). Thus, hypoxia leads to the development of resistance to conventional therapies. Therefore, the fabrication of a nanoscale porous system enriched with upconversion nanoparticles to target cancer cells, evade hypoxia, and enhance anticancer therapy is the key goal of this article. Herein, upconversion nanoparticles are embedded in a nanoscale porous organic polymer (POP) and further conjugated with a targeting moiety and a catalase molecule. The nanoscale POP embedded in UCNPs is generated at room temperature. The targeting ligand, lactobionic acid, is attached after polymer coating, which effectively targets liver cancer cells. Then, catalase is grafted effectively to produce oxygen. Endogenously generated oxygen alleviates hypoxia in liver cancer cells. The drug- and catalase-loaded composite exhibit greater cytotoxicity in hypoxic liver cells than in normal cells by overcoming hypoxia and downregulating the hypoxia-inducible factors.

Natural Products and Derivatives Targeting Metabolic Reprogramming in Colorectal Cancer: A Comprehensive Review.

Metabolic reprogramming is a critical pathogenesis of colorectal cancer (CRC), referring to metabolic disorders that cancer cells make in response to the stimulating pressure. Metabolic reprogramming induces changes in genetic material and promotes CRC progression and has been proven to be an efficient target of CRC. As natural products have garnered interest due to notable pharmacological effects and potential in counteracting chemoresistance, an increasing body of research is delving into the impact of these natural products on the metabolic reprogramming associated with CRC. In this review, we collected published data from the Web of Science and PubMed, covering the period from January 1980 to October 2023. This article focuses on five central facets of metabolic alterations in cancer cells, glucose metabolism, mitochondrial oxidative phosphorylation (OXPHOS), amino acid metabolism, fatty acid synthesis, and nucleotide metabolism, to provide an overview of recent advancements in natural product interventions targeting metabolic reprogramming in CRC. Our analysis underscores the potential of natural products in disrupting the metabolic pathways of CRC, suggesting promising therapeutic targets for CRC and expanding treatment options for metabolic-associated ailments.

Metabolomics and cellular altered pathways in cancer biology: A review.

Cancer is a deadly disease that affects a cell's metabolism and surrounding tissues. Understanding the fundamental mechanisms of metabolic alterations in cancer cells would assist in developing cancer treatment targets and approaches. From this perspective, metabolomics is a great analytical tool to clarify the mechanisms of cancer therapy as well as a useful tool to investigate cancer from a distinct viewpoint. It is a powerful emerging technology that detects up to thousands of molecules in tissues and biofluids. Like other "-omics" technologies, metabolomics involves the comprehensive investigation of micromolecule metabolites and can reveal important details about the cancer state that is otherwise not apparent. Recent developments in metabolomics technologies have made it possible to investigate cancer metabolism in greater depth and comprehend how cancer cells utilize metabolic pathways to make the amino acids, nucleotides, and lipids required for tumorigenesis. These new technologies have made it possible to learn more about cancer metabolism. Here, we review the cellular and systemic effects of cancer and cancer treatments on metabolism. The current study provides an overview of metabolomics, emphasizing the current technologies and their use in clinical and translational research settings.

Effect of polyphenols from kiwi by-products (PKWP) on redox and metabolic homeostasis of HepG2 cells

Polyphenols from kiwi by-products (PKWP) have been previously reported to have an inhibitory effect on cancer cells; but, the potential anti-cancer mechanism remains unknown. Metabolic alterations in cancer cells provide bioenergy and substances for uncontrolled proliferation and development, and interfering with the metabolic pathways has been regarded as effective in impeding cancer progression. Cancer cells are also characterised by a relatively higher level of oxidative stress and an enhanced antioxidant defence system, facilitating multiple stages of tumorigenesis. Anti-cancer mechanisms of PKWP based on metabolic and redox homeostasis in HepG2 cells were thus investigated in the present work. The results showed that PKWP effectively decreased HepG2 cell viability in a concentration-dependent manner. PKWP caused metabolic disorders in HepG2 cells, and significantly affected the content of about 32 metabolites. PKWP mainly inhibited saccharide synthesis and glycolysis, and restricted the utilisation of amino acids. PKWP stimulated ROS production, and caused lipid peroxidation, resulting in oxidative damage. PKWP also down-regulated the activities of T-SOD and CAT, and the level of GSH, and inhibited the protein expressions of HO-1 and COX-2, weakening the cellular antioxidant capacity. Thus, PKWP could exert prominent anti-cancer activity in HepG2 cells by disrupting metabolic homeostasis, and induction of oxidative stress. These findings will provide evidence for further elucidation of the anti-cancer mechanism of PKWP, and the potential application of PKWP as a natural ingredient in functional food, cosmetic, and pharmaceutical industries.

Unveiling the altered metabolic pathways induced by nivolumab in non-small cell lung cancer via GC–MS metabolomics approach coupled with multivariate analysis

This research investigates the effects of the immunotherapeutic agent nivolumab on the metabolism of lung cancer cells (NCI-H1975) using GC–MS metabolomic profiling. Multivariate analysis such as unsupervised PCA and supervised OPLS-DA along with univariate analysis and pathway analysis were employed to explore the metabolomic data and identify altered metabolic pathways induced by nivolumab treatment. The study revealed distinct metabolic alterations in cancer cells, linked to proliferative and survival advantages, such as enhanced glycolysis, increased glutaminolysis, and modified amino acid metabolism. Key findings indicate elevated levels of glycolysis-related metabolites (glycine, alanine, pyruvate, and lactate) and TCA cycle intermediates (succinate, fumarate, malate) in cancer cells, with a significant decrease following nivolumab treatment. Additionally, lower levels of aspartic acid and citrate in cancer cells imply altered nucleotide synthesis and fatty acid production essential for tumor growth. Treatment with nivolumab also reduced oleic acid levels, indicative of its effect on disrupted lipid metabolism. Our research shows nivolumab's potential to modify metabolic pathways involved in lung cancer progression, suggesting its dual role in cancer therapy: as an immune response modulator and a metabolic pathway disruptor.

Chitosan lecithin nanocomposite based electrochemical biosensor for glycine detection in biological matrices

Increased glycine concentrations are associated with altered metabolism of cancer cells and is reflected in the bodily fluids of the brain cancer patients. Various studies have been conducted in past to detect glycine as an imaging biomarker via NMR Spectroscopy tools. However, the use is limited because of the low concentration and different in vivo detection due to overlapping of peaks with myo-inositol in same spectral position. Alongside, little is known about the electrochemical potential of Glycine as a biomarker for brain cancer. The prime impetus of this study was to check the feasibility of glycine as non-invasive biomarker for brain cancer. A divergent approach to detect glycine “non-enzymatically” via unique chitosan lecithin nanocomposite has been utilised during this study. The electrochemical inactivity at provided potential that prevented glycine to get oxidized or reduced without mediator was compensated utilising the chitosan-lecithin nanocomposite. Thus, a redox mediator (Prussian blue) was used for high sensitivity and indirect detection of glycine. The chitosan nanoparticles-lecithin nanocomposite is used as a matrix. The electrochemical analysis of the onco-metabolomic biomarker (glycine) utilizing cyclic voltammetry in glycine spiked multi-Purpose artificial urine was performed to check distribution of glycine over physiological range of glycine. A wide linear range of response varying over the physiological range from 7 to 240 μM with a LOD 8.5 μM was obtained, showing potential of detection in biological samples. We have further evaluated our results via simulating the interaction of mediator and matrix with Glycine by HOMO-LUMO band fluctuations.

Regulation of Hypoxia Dependent Reprogramming of Cancer Metabolism: Role of HIF-1 and Its Potential Therapeutic Implications in Leukemia.

Metabolic reprogramming occurs to meet cancer cells' high energy demand. Its function is essential to the survival of malignancies. Comparing cancer cells to non-malignant cells has revealed that cancer cells have altered metabolism. Several pathways, particularly mTOR, Akt, PI3K, and HIF-1 (hypoxia-inducible factor-1) modulate the metabolism of cancer. Among other aspects of cancer biology, gene expression in metabolism, survival, invasion, proliferation, and angiogenesis of cells are controlled by HIF-1, a vital controller of cellular responsiveness to hypoxia. This article examines various cancer cell metabolisms, metabolic alterations that can take place in cancer cells, metabolic pathways, and molecular aspects of metabolic alteration in cancer cells placing special attention on the consequences of hypoxia-inducible factor and summarising some of their novel targets in the treatment of cancer including leukemia. A brief description of HIF-1α's role and target in a few common types of hematological malignancies (leukemia) is also elucidated in the present article.

Abstract 1557: Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4

Abstract Metastatic disease is the main cause of cancer death, and the brain is one of the major sites of breast tumor metastasis. The median survival of breast cancer patients who developed brain metastases (BrM) is less than a year even with the advanced treatment such as stereotactic radiosurgery (SRS). Regardless of high clinical significance, the pathological mechanism of brain metastasis is still poorly understood. Previously, we found that loss of lncRNA XIST robustly promote metastasis and specially brain metastasis in breast cancer. However, the underlying molecular mechanism was not fully understood. In following study, we found that loss of XIST has significantly altered lipid metabolism of breast cancer cells specifically increasing lipid droplet amount and PUFA incorporation. Instead of de novo syntheses, XISTlow cancer cells acquire fatty acid by uptake from exogenous. We found that one X-linked gene, Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) which are highly upregulated after loss of XIST is responsible for the altered lipid metabolism. ACSL4 activated the free polyunsaturated fatty acids (PUFAs) and lead to increased incorporation of PUFAs into phospholipids. On one hand, elevated ACLS4 expression leads to relative low PPAR pathway activation by decreasing the cellular free PUFA level which directly binds and activate PPAR. PPAR pathway is known to inhibit the expression of inflammatory cytokines which are important for cancer cells to establish brain metastasis. On the other hand, elevated ACSL4 expression enable cancer cells to metabolize the abundant PUFAs in the brain environment, thereby gaining survival advantage. However, increased PUFA incorporation into lipids especially phospholipids produce excess lipid ROS and sensitize cells to ferroptosis inducer such as RSL3. Our study has find out that brain microenvironment not only supports the outgrowth of XIST low cells by providing PUFAs for maintaining their metastatic properties but also sensitizes those cells to ferroptosis inducers, a potential therapy for treating this devastating disease. Citation Format: Yin Liu, Margaret R. Smith, Yuezhu Wang, Ralph D’Agostino, Jimmy Ruiz, Gregory L. Kucera, Lance D. Miller, Wencheng Li, Michael D. Chan, Michael Farris, Dawen Zhao, Fei Xing. Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1557.

Hacking the Lipidome: New Ferroptosis Strategies in Cancer Therapy.

The concept of redirecting metabolic pathways in cancer cells for therapeutic purposes has become a prominent theme in recent research. Now, with the advent of ferroptosis, a new chink in the armor has evolved that allows for repurposing of ferroptosis-sensitive lipids in order to trigger cell death. This review presents the historical context of lipidomic and metabolic alterations in cancer cells associated with ferroptosis sensitization. The main proferroptotic genes and pathways are identified as therapeutic targets for increasing susceptibility to ferroptosis. In this review, a particular emphasis is given to pathways in cancer cells such as de novo lipogenesis, which has been described as a potential target for ferroptosis sensitization. Additionally, we propose a connection between ketolysis inhibition and sensitivity to ferroptosis as a new vulnerability in cancer cells. The main proferroptotic genes and pathways have been identified as therapeutic targets for increasing susceptibility to ferroptosis. Proferroptotic metabolic pathways and vulnerable points, along with suggested agonists or antagonists, are also discussed. Finally, general therapeutic strategies for ferroptosis sensitization based on the manipulation of the lipidome in ferroptosis-resistant cancer cell lines are proposed.

On the Origin of the Warburg Effect in Cancer Cells: Controlling Cancer as a Metabolic Disease

Background: Human cells may switch metabolism from aerobic to anaerobic or vice versa depending on cellular conditions. The use of anaerobic cellular respiration is especially common in cells with metabolic disorders such as cancer cells. However, despite the fact that metabolic alteration in cancer cells is well-established, its cause is still not well understood. Objective: The purpose of this study is to address the origin of abnormal behavior and metabolic changes in cancer cells to better understand the processes that are involved in the formation and spread of cancer.Methods: This paper reviews and explains key concepts related to the evolutionary origin of key metabolic pathways in cancer cells, considering the behavioral similarities between cancer cells and ancient unicellular organisms. The evaluations help better understand the Warburg effect and the related cancer control strategies.Results: The risk of cancer may be reduced by creating suitable and optimal conditions at the cellular level, which can increase the chance of cell survival in the event of cellular stress. This may be achieved through dietary and lifestyle modifications, such as adopting a balanced natural diet that meets cellular needs in a way that leads to cancer control. Conclusions: Understanding the biological origin and causes of cancer initiation and development is essential for the metabolic control of cancer as well as for improving therapeutic strategies.

MiR-140-5p regulates the hypoxia-mediated oxidative stress through Nrf2

Rapid and uncontrollable cell proliferation, altered metabolism, and abnormal vasculature of cancer cells make them hypoxic and result in the generation of reactive oxygen species (ROS), causing oxidative stress. Hypoxia-mediated oxidative stress represents a significant barrier to effective cancer treatment. miRNAs are emerging as a potential regulator of hypoxia-responsive genes and hypoxia-mediated oxidative stress. Based on the role of miR-140-5p in regulating a hypoxia-responsive gene, this study is aimed at understanding the miR-140-5p role in regulating hypoxia-mediated oxidative stress under breast tumor hypoxia. We found that the miR-140-5p might control the hypoxia-mediated ROS generation by regulating the Nrf2 expression. Knowing the significance of miR-140-5p in regulating hypoxia-mediated oxidative stress and breast tumor progression, targeting miR-140-5p might represent a promising strategy for anti-breast cancer therapy.

The amino acid transporter SLC7A11 expression in breast cancer

ABSTRACTBreast cancer (BC), characterized by its diverse molecular profiles and clinical outcomes, presents a significant challenge in the development of effective therapeutic strategies. Metabolic reprogramming, a defining characteristic of cancer, has emerged as a promising target for novel therapies. SLC7A11, an amino acid transporter that facilitates cysteine uptake in exchange for glutamate, plays a crucial role in sustaining the altered metabolism of cancer cells. This study delves into the comprehensive analysis of SLC7A11 at the genomic, transcriptomic, and protein levels in extensive BC datasets to elucidate its potential role in different BC subtypes. SLC7A11 gene copy number and mRNA expression were evaluated using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1,980) and Breast Cancer Gene Expression Miner (n = 4,712). SLC7A11 protein was assessed using immunohistochemistry in a large BC cohort (n = 1,981). Additionally, The Cancer Genome Atlas (TCGA) dataset was used to explore SLC7A11 DNA methylation patterns using MethSurv (n = 782) and association of SLC7A11 mRNA expression with immune infiltrates using TIMER (n = 1,100). High SLC7A11 mRNA and SLC7A11 protein expression were significantly associated with high tumor grade (p ≤ .02), indicating a potential role in cancer progression. Interestingly, SLC7A11 copy number gain was observed in HER2+ tumors (p = .01), suggesting a subtype-specific association. In contrast, SLC7A11 mRNA expression was higher in the basal-like/triple-negative (TN; p < .001) and luminal B tumors (p = .02), highlighting its differential expression across BC subtypes. Notably, high SLC7A11 protein expression was predominantly observed in Estrogen Receptor (ER)-negative and Triple Negative (TN) BC, suggesting a role in these aggressive subtypes. Further analysis revealed that SLC7A11 was positively correlated with other amino acid transporters and enzymes associated with glutamine metabolism, implying a coordinated role in metabolic regulation. Additionally, SLC7A11 gene expression was positively associated with neutrophil and macrophage infiltration, suggesting a potential link between SLC7A11 and tumor immunity. Our findings suggest that SLC7A11 plays a significant role in BC metabolism, demonstrating differential expression across subtypes and associations with poor patient outcomes. Further functional studies are warranted to elucidate the precise mechanisms by which SLC7A11 contributes to BC progression and to explore its potential as a therapeutic target.

The Illustration of Altered Glucose Dependency in Drug-Resistant Cancer Cells.

A chemotherapeutic approach is crucial in malignancy management, which is often challenging due to the development of chemoresistance. Over time, chemo-resistant cancer cells rapidly repopulate and metastasize, increasing the recurrence rate in cancer patients. Targeting these destined cancer cells is more troublesome for clinicians, as they share biology and molecular cross-talks with normal cells. However, the recent insights into the metabolic profiles of chemo-resistant cancer cells surprisingly illustrated the activation of distinct pathways compared with chemo-sensitive or primary cancer cells. These distinct metabolic dynamics are vital and contribute to the shift from chemo-sensitivity to chemo-resistance in cancer. This review will discuss the important metabolic alterations in cancer cells that lead to drug resistance.

Investigating ionizing radiation-induced changes in breast cancer cells using stimulated Raman scattering microscopy.

Altered lipid metabolism of cancer cells has been implicated in increased radiation resistance. A better understanding of this phenomenon may lead to improved radiation treatment planning. Stimulated Raman scattering (SRS) microscopy enables label-free and quantitative imaging of cellular lipids but has never been applied in this domain. We sought to investigate the radiobiological response in human breast cancer MCF7 cells using SRS microscopy, focusing on how radiation affects lipid droplet (LD) distribution and cellular morphology. MCF7 breast cancer cells were exposed to either 0 or 30Gy (X-ray) ionizing radiation and imaged using a spectrally focused SRS microscope every 24hrs over a 72-hr time period. Images were analyzed to quantify changes in LD area per cell, lipid and protein content per cell, and cellular morphology. Cell viability and confluency were measured using a live cell imaging system while radiation-induced lipid peroxidation was assessed using BODIPY C11 staining and flow cytometry. The LD area per cell and total lipid and protein intensities per cell were found to increase significantly for irradiated cells compared to control cells from 48 to 72hrs post irradiation. Increased cell size, vacuole formation, and multinucleation were observed as well. No significant cell death was observed due to irradiation, but lipid peroxidation was found to be greater in the irradiated cells than control cells at 72hrs. This pilot study demonstrates the potential of SRS imaging for investigating ionizing radiation-induced changes in cancer cells without the use of fluorescent labels.

Intrinsic features of the cancer cell as drivers of immune checkpoint blockade response and refractoriness.

Immune checkpoint blockade represents the latest revolution in cancer treatment by substantially increasing patients' lifetime and quality of life in multiple neoplastic pathologies. However, this new avenue of cancer management appeared extremely beneficial in a minority of cancer types and the sub-population of patients that would benefit from such therapies remain difficult to predict. In this review of the literature, we have summarized important knowledge linking cancer cell characteristics with the response to immunotherapy. Mostly focused on lung cancer, our objective was to illustrate how cancer cell diversity inside a well-defined pathology might explain sensitivity and refractoriness to immunotherapies. We first discuss how genomic instability, epigenetics and innate immune signaling could explain differences in the response to immune checkpoint blockers. Then, in a second part we detailed important notions suggesting that altered cancer cell metabolism, specific oncogenic signaling, tumor suppressor loss as well as tight control of the cGAS/STING pathway in the cancer cells can be associated with resistance to immune checkpoint blockade. At the end, we discussed recent evidences that could suggest that immune checkpoint blockade as first line therapy might shape the cancer cell clones diversity and give rise to the appearance of novel resistance mechanisms.

Oncogene-mediated nuclear accumulation of lactate promotes epigenetic alterations to induce cancer cell proliferation.

Homeobox gene families are associated with embryonic development and organogenesis. Pieces of evidence suggest that these Homeobox genes are also crucial in facilitating oncogenesis when mutated or overexpressed. Paired homeodomain transcription factor-2 (PITX2), one of the members of this family, is involved in oncogenic regulation apart from its different development regulatory functions. PITX2 has been earlier shown to induce ovarian cancer cell proliferation through the activation of different signaling cascades. Increased cancer cell proliferation requires a constant supply of nutrients for both adenosine triphosphate and biomass synthesis, which is facilitated by altered cancer cell metabolism that includes enhanced glucose uptake and increased glycolytic rate. This present study highlights the involvement of PITX2 in enhancing the cellular glycolysis pathway in ovarian cancer cells through protein kinase B-phosphorylation (phospho-AKT). PITX2 expression correlates positively with that of the glycolytic rate-determining enzyme, lactate dehydrogenase-A (LDHA), in both high-grade serous ovarian cancer tissues and common ovarian cancer cell lines. Interestingly, transient localization of enzymatically active LDHA in the nucleus was observed in PITX2-overexpressed ovarian cancer cells. This nuclear LDHA produces higher concentrations of the glycolytic end product, lactate, which accumulates in the nuclear compartment resulting in decreased histone deacetylase (HDAC1/2) expression and increased histone acetylation at H3/H4. However, the mechanistic details of lactate-HDAC interaction are still elusive in the earlier reports. Our in silico studies elaborated on the interaction dynamics of lactate in the HDAC catalytic core through ligand-binding studies and molecular dynamics simulation approaches. Blocking lactate production by silencing LDHA reduced cancer cell proliferation. Thus, PITX2-induced epigenetic changes can lead to high cellular proliferation and increase the size of tumors in syngeneic mice as well. Taken together, this is the first report of its kind to show that the developmental regulatory homeobox gene PITX2 could enhance oncogenesis through enhanced glycolysis of tumor cells followed by epigenetic modifications.

3D Chemical Imaging by Fluorescence-detected Mid-Infrared Photothermal Fourier Light Field Microscopy.

Three-dimensional molecular imaging of living organisms and cells plays a significant role in modern biology. Yet, current volumetric imaging modalities are largely fluorescence-based and thus lack chemical content information. Mid-infrared photothermal microscopy as a chemical imaging technology provides infrared spectroscopic information at submicrometer spatial resolution. Here, by harnessing thermosensitive fluorescent dyes to sense the mid-infrared photothermal effect, we demonstrate 3D fluorescence-detected mid-infrared photothermal Fourier light field (FMIP-FLF) microscopy at the speed of 8 volumes per second and submicron spatial resolution. Protein contents in bacteria and lipid droplets in living pancreatic cancer cells are visualized. Altered lipid metabolism in drug-resistant pancreatic cancer cells is observed with the FMIP-FLF microscope.

Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma.

Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas.

When cancer drug resistance meets metabolomics (bulk, single-cell and/or spatial): Progress, potential, and perspective.

Resistance to drug treatment is a critical barrier in cancer therapy. There is an unmet need to explore cancer hallmarks that can be targeted to overcome this resistance for therapeutic gain. Over time, metabolic reprogramming has been recognised as one hallmark that can be used to prevent therapeutic resistance. With the advent of metabolomics, targeting metabolic alterations in cancer cells and host patients represents an emerging therapeutic strategy for overcoming cancer drug resistance. Driven by technological and methodological advances in mass spectrometry imaging, spatial metabolomics involves the profiling of all the metabolites (metabolomics) so that the spatial information is captured bona fide within the sample. Spatial metabolomics offers an opportunity to demonstrate the drug-resistant tumor profile with metabolic heterogeneity, and also poses a data-mining challenge to reveal meaningful insights from high-dimensional spatial information. In this review, we discuss the latest progress, with the focus on currently available bulk, single-cell and spatial metabolomics technologies and their successful applications in pre-clinical and translational studies on cancer drug resistance. We provide a summary of metabolic mechanisms underlying cancer drug resistance from different aspects; these include the Warburg effect, altered amino acid/lipid/drug metabolism, generation of drug-resistant cancer stem cells, and immunosuppressive metabolism. Furthermore, we propose solutions describing how to overcome cancer drug resistance; these include early detection during cancer initiation, monitoring of clinical drug response, novel anticancer drug and target metabolism, immunotherapy, and the emergence of spatial metabolomics. We conclude by describing the perspectives on how spatial omics approaches (integrating spatial metabolomics) could be further developed to improve the management of drug resistance in cancer patients.

The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression.

Metabolic reprogramming is an important cancer hallmark. However, the mechanisms driving metabolic phenotypes of cancer cells are unclear. Here, we showed that the interferon (IFN)-inducible protein, viperin, drives metabolic alteration in cancer cells. Viperin was observed in various types of cancer and inversely correlated with the survival rate of patients with gastric, lung, breast, renal, pancreatic, or brain cancer. By generating viperin knockdown or stably expressing cancer cells, we showed that viperin, but not a mutant lacking its iron-sulfur cluster-binding motif, increased lipogenesis and glycolysis via inhibition of fatty acid β-oxidation in cancer cells. In the tumor microenvironment, deficiency of fatty acids and oxygen as well as production of IFNs upregulated viperin expression via the PI3K/AKT/mTOR/HIF-1α and JAK/STAT pathways. Moreover, viperin was primarily expressed in cancer stem-like cells (CSCs) and functioned to promote metabolic reprogramming and enhance CSC properties, thereby facilitating tumor growth in xenograft mouse models. Collectively, our data indicate that viperin-mediated metabolic alteration drives the metabolic phenotype and progression of cancer.