Tumor Metabolic Reprogramming Research Articles

LncRNAs in tumor metabolic reprogramming and tumor microenvironment remodeling.

The tumor microenvironment (TME) is a complex and dynamic ecosystem composed of tumor cells, immune cells, supporting cells, and the extracellular matrix. Typically, the TME is characterized by an immunosuppressive state. To meet the demands of rapid proliferation, cancer cells undergo metabolic reprogramming, which enhances their biosynthesis and bioenergy supply. Immune cells require similar nutrients for activation and proliferation, leading to competition and immunosuppression within the TME. Additionally, tumor metabolites inhibit immune cell activation and function. Consequently, an immunosuppressed and immune-tolerant TME promotes cancer cell proliferation and metastasis. Long non-coding RNAs (lncRNAs), a category of non-coding RNA longer than 200 nucleotides, regulate tumor metabolic reprogramming by interacting with key enzymes, transporters, and related signaling pathways involved in tumor metabolism. Furthermore, lncRNAs can interact with both cellular and non-cellular components in the TME, thereby facilitating tumor growth, metastasis, drug resistance, and inducing immunosuppression. Recent studies have demonstrated that lncRNAs play a crucial role in reshaping the TME by regulating tumor metabolic reprogramming. In this discussion, we explore the potential mechanisms through which lncRNAs regulate tumor metabolic reprogramming to remodel the TME. Additionally, we examine the prospects of lncRNAs as targets for anti-tumor therapy and as biomarkers for tumor prognosis.

MICU2 up-regulation enhances tumor aggressiveness and metabolic reprogramming during colorectal cancer development.

The mitochondrial Ca2+ uniporter (MCU) plays crucial role in intramitochondrial Ca2+ uptake, allowing Ca2+-dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and invasion using in vitro and in vivo models of human colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca2+ uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming.

Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer

BackgroundCurrent evidence underlines the active role of neural infiltration and axonogenesis within the tumor microenvironment (TME), with implications for tumor progression. Infiltrating nerves stimulate tumor growth and dissemination by secreting neurotransmitters, whereas tumor cells influence nerve growth and differentiation through complex interactions, promoting tumor progression. However, the role of neural infiltration in the progression of non-small cell lung cancer (NSCLC) remains unclear.MethodsThis study employs the techniques of immunohistochemistry, immunofluorescence, RNA sequencing, molecular biology experiments, and a murine orthotopic lung cancer model to deeply analyze the specific mechanisms behind the differential efficacy of NSCLC immunotherapy from the perspectives of neuro-tumor signal transduction, tumor metabolism, and tumor immunity.ResultsThis study demonstrates that nerve growth factor (NGF) drives neural infiltration in NSCLC, and 5-hydroxytryptamine (5-HT), which is secreted by nerves, is significantly elevated in tumors with extensive neural infiltration. Transcriptome sequencing revealed that 5-HT enhanced glycolysis in NSCLC cells. Pathway analysis indicated that 5-HT activated the PI3K/Akt/mTOR pathway, promoting tumor metabolic reprogramming. This reprogramming exacerbated immunosuppression in the TME. Neutralizing 5-HT-mediated metabolic reprogramming in tumor immunity enhanced the efficacy of PD-1 monoclonal antibody treatment in mice.ConclusionsThe findings of this study provide a novel perspective on the crosstalk between nerves and lung cancer cells and provide insights into further investigations into the role of nerve infiltration in NSCLC progression.

Berberine modulates ovarian cancer autophagy and glycolysis through the LINC01123/P65/MAPK10 signaling axis

BackgroundBerberine, a readily accessible natural compound known for its ease of synthesis and low toxicity, exhibits anti-tumor properties by modulating inflammatory responses. Recent studies have revealed that berberine can also treat malignant tumors by influencing tumor metabolic reprogramming, making it a potential candidate for metabolic therapy in ovarian cancer. MethodsThe anti-proliferative and anti-metastatic effects of berberine on ovarian cancer cells were investigated using CCK-8 assays, scratch assays, EDU proliferation assays, and assays related to glycolysis and autophagy. Differentially expressed lncRNAs in ovarian cancer were identified using data from the TCGA database. A specific lncRNA's role was delineated through RNA pulldown assays, silver staining, mass spectrometry analysis, CHIP assays, and immunoprecipitation experiments, focusing on its involvement in glycolysis and autophagy regulation in ovarian cancer. Additionally, the inhibitory mechanism of berberine on ovarian cancer cells was validated through cell thermal shift assays and cycloheximide protein degradation experiments to confirm its interaction with key targets. ResultsIn vitro experiments revealed that berberine reduces glycolysis and autophagy levels, leading to the inhibition of ovarian cancer cell proliferation and metastasis. Bioinformatics analysis of TCGA data identified LINC00123 as associated with poor prognosis in ovarian cancer. Experimental validation, including RNA pulldown assays, confirmed that the LINC00123/P65/MAPK10 signaling axis regulates glycolysis and autophagy in ovarian cancer. Furthermore, at the molecular level, berberine inhibits the interaction between LINC00123 and P65, thereby reducing P65 protein stability and impeding its transcriptional regulation of downstream MAPK10. These findings were further validated in animal models. ConclusionOur study highlights berberine's dual benefits of anti-inflammatory effects and inhibition of ovarian cancer proliferation and metastasis by modulating autophagy and glycolysis levels. Mechanistically, berberine targets the LINC00123/P65/MAPK10 signaling pathway to regulate glycolysis and autophagy in ovarian cancer. These insights not only expand the potential of berberine in ovarian cancer therapy but also provide new targets and therapeutic strategies for metabolic therapy in this cancer type.

PYGB targeted by androgen receptor contributes to tumor progression and metabolic reprogramming in esophageal squamous carcinoma

BackgroundThe incidence and mortality rates of esophageal squamous cell carcinoma (ESCC) are conspicuously augmented in men in contrast to women. The androgen receptor (AR), prevalently associated with the manifestation of male characteristics, is regarded as a pivotal determinant in tumor progression. Nevertheless, its exact role in ESCC remains insufficiently delineated. MethodsIn this study, we probed the expression levels of AR and glucose metabolism enzymes in ESCC tissues by means of immunohistochemistry. We exploited chromatin immunoprecipitation and dual luciferase reporter assays to delve into the transcriptional regulatory interrelationships between AR and these enzymes. A gamut of molecular techniques—including multi-omics sequencing, colony formation assays, cell counting kit 8 (CCK8), 5-Ethynyl-2′-deoxyuridine (EdU) incorporation assays, wound-healing assays, transwell migration assays, extracellular acidification rate (ECAR) measurements, lipid droplet fluorescence imaging, and xenograft models—were enlisted to illuminate the functions of these enzymes within ESCC cells. ResultsOur discoveries manifested that AR expression was strikingly higher in male ESCC tissues than in their female counterparts. Significantly, we discerned that glycogen phosphorylase B (PYGB), a cardinal enzyme implicated in glucose metabolism, demonstrated not only a positive correlation with AR expression but also an association with adverse prognostic outcomes for ESCC patients. Moreover, AR directly binds to the promoter region of the PYGB gene, thereby potentiating its transcriptional activity. This upregulation of PYGB was ascertained to facilitate proliferation, invasion, and metastasis among ESCC cells while intensifying glycolysis and modifying lipid metabolism pathways within these cells. In animal models employing nude mice, elevated PYGB levels were witnessed to expedite subcutaneous tumor growth as well as lung metastasis. ConclusionsCollectively, our study establishes PYGB as a direct target of AR that assumes an indispensable role in both tumor progression and metabolic reprogramming affiliated with ESCC, thus paving novel avenues for therapeutic strategies centered on metabolic intercessions.

Effect of ZCRB1 on the glycolysis via PKM2-HIF1α axis and promotion of immune tolerance in nasopharyngeal carcinoma.

130 Background: Nasopharyngeal carcinoma (NPC) is characterized by abundant lymphocyte infiltration. The failure of immune checkpoint inhibitors in NPC may be related to immune tolerance. Methods: Bioinformatics analysis was performed to identify the correlation between the ZCRB1 mRNA level and immune cell infiltration in NPC tissues. Quantitative real time PCR and immunoblotting were used to determine the mRNA and protein expression, respectively. Functional experiments (CCK8, colony formation assay, cell migration assay and tumor xenograft) were used to explore the effect of ZCRB1 on the malignant phenotype in NPC cells. Glucose and lactate measurement assays as well as Seahorse XF glycolysis stress assay, were conducted to investigate the effects of ZCRB1 on glycolysis in NPC cells. RNA sequencing, QPCR and minigene analysis were used to confirm the splicing switch between PKM1 and PKM2. Luciferase assay was performed to detect the transcription activity of HIF1-α. Finally, correlation analysis between the ZCRB1 expression and glycolysis level was performed to in NPC samples. Results: The expression of ZCRB1 was negatively correlated with checkpoint-related genes and immune regulation-related gene sets in head and neck cancer. Likewise, in NPC, the expression of ZCRB1 was negatively correlated with lymphocyte infiltration, tumor immune microenvironment score and tumor-infiltrating CD4+ T cells, CD8+ T cells, and dendritic cells. Low expression of ZCRB1 was associated with better prognosis. Functional assays demonstrated that ZCRB1 significantly promoted NPC cells growth, clonogenicity, migratory capacity and glycolysis. Mechanistically, ZCRB1 was mainly involved in the hypoxic signaling pathway. Cells with ZCRB1 downregulation downregulated glycolysis-related genes and significantly reduced the transcriptional activity of HIF-1α. Moreover, minigene assays showed that the intron 9 region spliced by PKM in cells with ZCRB1 downregulation. Finally, bioinformatics analysis showed that the mRNA expression of ZCRB1 was positively correlated with the immune infiltration score significantly during glycolysis. Conclusions: ZCRB1 promotes the growth and migration of nasopharyngeal carcinoma cells and is associated with immune tolerance. Further, ZCRB1 accelerates the glycolysis via enhancing the transcriptional activity of HIF-1α through increasing PKM2 isoform splicing, providing a scientific basis for tumor metabolic reprogramming to reshape the immune microenvironment.

Targeting the Hippo/YAP1 signaling pathway in hepatocellular carcinoma: From mechanisms to therapeutic drugs (Review).

The Hippo signaling pathway plays a pivotal role in regulating cell growth and organ size. Its regulatory effects on hepatocellular carcinoma (HCC) encompass diverse aspects, including cell proliferation, invasion and metastasis, tumor drug resistance, metabolic reprogramming, immunomodulatory effects and autophagy. Yes‑associated protein 1 (YAP1), a potent transcriptional coactivator and a major downstream target tightly controlled by the Hippo pathway, is influenced by various molecules and pathways. The expression of YAP1 in different cell types within the liver tumor microenvironment exerts varying effects on tumor outcomes, warranting careful consideration. Therefore, research on YAP1‑targeted therapies merits attention. This review discusses the composition and regulation mechanism of the Hippo/YAP1 signaling pathway and its relationship with HCC, offering insights for future research and cancer prevention strategies.

Metabolic reprogramming in hepatocellular carcinoma: a bibliometric and visualized study from 2011 to 2023.

Metabolic reprogramming has been found to be a typical feature of tumors. Hepatocellular carcinoma (HCC), a cancer with high morbidity and mortality, has been extensively studied for its metabolic reprogramming-related mechanisms. Our study aims to identify the hotspots and frontiers of metabolic reprogramming research in HCC and to provide guidance for future scientific research and decision-making in HCC metabolism. Relevant studies on the metabolic reprogramming of HCC were derived from the Web of Science Core Collection (WoSCC) database up until November 2023. The bibliometrix tools in R were used for scientometric analysis and visualization. From 2011 to 2023, a total of 575 publications were obtained from WoSCC that met the established criteria. These publications involved 3,904 researchers and 948 organizations in 37 countries, with an average annual growth rate of 39.11% in research. These studies were published in 233 journals, with Cancers (n = 29) ranking first, followed by Frontiers in Oncology (n = 20) and International Journal of Molecular Sciences (n = 19). The top ten journals accounted for 26% of the 575 studies. The most prolific authors were Wang J (n = 14), Li Y (n = 12), and Liu J (n = 12). The country with the most publications is China, followed by the United States, Italy, and France. Fudan University had the largest percentage of research results with 15.48% (n = 89). Ally A's paper in Cell has the most citations. A total of 1,204 keywords were analyzed, with the trend themes such as "glycolysis," "tumor microenvironment," "Warburg effect," "mitochondria," "hypoxia ," etc. Co-occurrence network and cluster analysis revealed the relationships between keywords, authors, publications, and journals. Moreover, the close collaboration between countries in this field was elucidated. This bibliometric and visual analysis delves into studies related to metabolic reprogramming in HCC between 2012 and 2023, elucidating the characteristics of research in this field, which has gradually moved away from single glycolipid metabolism studies to the integration of overall metabolism in the body, pointing out the trend of research topics, and the dynamics of the interaction between the tumor microenvironment and metabolic reprogramming will be the future direction of research, which provides blueprints and inspirations for HCC prevention and treatment programs to the researchers in this field.

Emerging roles of tripartite motif family proteins (TRIMs) in breast cancer.

Breast cancer (BC) is the most common malignant tumor worldwide. Despite enormous progress made in the past decades, the underlying mechanisms of BC remain further illustrated. Recently, TRIM family proteins proved to be engaged in BC progression through regulating various aspects. Here we reviewed the structures and basic functions of TRIM family members and first classified them into three groups according to canonical polyubiquitination forms that they could mediate: K48- only, K63- only, and both K48- and K63-linked ubiquitination. Afterwards, we focused on the specific biological functions and mechanisms of TRIMs in BCs, including tumorigenesis and invasiveness, drug sensitivity, tumor immune microenvironment (TIME), cell cycle, and metabolic reprogramming. We also explored the potential of TRIMs as novel biomarkers for predicting prognosis and future therapeutic targets in BC.

Tumor microenvironment activation amplify oxidative stress promoting tumor energy remodeling for mild photothermal therapy and cuproptosis

Tumor metabolic reprogramming requires high levels of adenosine triphosphate (ATP) to maintain treatment resistance, which poses major challenges to chemotherapy and photothermal therapy. Especially, high levels of ATP promote copper ion efflux for limiting the curative effect of cuproptosis. Here, an H2S-responsive mesoporous Cu2Cl(OH)3-loading chemotherapeutic cisplatin (CDDP) was synthesized, and the final nanoparticle, CDDP@Cu2Cl(OH)3-CDs (CDCuCDs), was encapsulated by electrostatic action with carbon dots (CDs). CDCuCDs reacted with overproduction H2S in colon tumor to produce photothermic copper sulfide for photothermal therapy. CDDP was released by lysis to achieve chemotherapeutic effects. Importantly, CDDP elevated H2O2 levels in cells through a cascade reaction and continuously transforms H2O2 into highly cytotoxic •OH through chemodynamic therapy between H2O2 and Cu+, which enables nanoparticles to generate •OH and improve the chemotherapeutic efficacy. Highly toxic •OH disrupts mitochondrial homeostasis, prohibiting it from performing normal energy-supplying functions. Down-regulated ATP inhibits heat shock protein expression, which promotes the therapeutic effect of mild photothermal therapy and reduces the efflux of intracellular copper ions, thus improving the therapeutic effect of cuproptosis. Our research provides a potential therapeutic strategy using overproduction H2S responses in tumors, allowing tumor microenvironment-activated •OH nanogenerators to promote tumor energy remodeling for cancer treatment.

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight.

Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. Moreover, metabolic reprogramming drives hepatocellular carcinoma (HCC) initiation and progression, highlighting the significance of metabolism in this disease. Exploring the inter-regulatory relationship between tumor metabolic reprogramming and epigenetic modification has become one of the hot directions in current tumor metabolism research. As viral etiologies have given way to metabolic dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it is urgent that complex molecular pathways linking them and hepatocarcinogenesis be explored. However, how aberrant crosstalk between epigenetic modifications and metabolic reprogramming affects MASLD-induced HCC lacks comprehensive understanding. A better understanding of their linkages is necessary and urgent to improve HCC treatment strategies. For this reason, this review examines the interwoven landscape of molecular carcinogenesis in the context of MASLD-induced HCC, focusing on mechanisms regulating aberrant epigenetic alterations and metabolic reprogramming in the development of MASLD-induced HCC and interactions between them while also updating the current advances in metabolism and epigenetic modification-based therapeutic drugs in HCC.

Multi-omics study on the molecular mechanism of anlotinib in regulating tumor metabolism.

e15121 Background: Anlotinib, an orally administered small molecule inhibitor of receptor tyrosine kinases (RTKs), exerts significant anti-angiogenic and vascular normalization effects. However, the mechanisms underlying its involvement in tumor metabolic reprogramming are still unclear. This study aims to investigate the distribution and expression levels of metabolites within tumors after anlotinib treatment using spatial metabolomics analysis. Methods: This study involves spatially analyzing the distribution differences of metabolites post-anlotinib administration and integrating transcriptomics and proteomics to explore the internal mechanisms of anlotinib action at a molecular level. Results: By integrating the transcriptomics and proteomics analyses, we identified that anlotinib treatment primarily modulated four metabolic pathways, including taurine and hypotaurine metabolism, steroid synthesis, pentose phosphate pathway, and lipid biosynthesis. This regulation significantly influenced the metabolic levels of compounds such as sulfonic acids, cholesterol, inositol phosphate pyrophosphate, and palmitoyl-CoA in the tumor, thereby impacting tumor initiation and progression. Conclusions: This study provides potential metabolic biomarkers for anlotinib treatment in tumors, and may identify potential biomarkers and pathways associated with the therapeutic efficacy of anlotinib treatment.

Bioinformatics and Experimental Study Revealed LINC00982/ miR-183-5p/ABCA8 Axis Suppresses LUAD Progression.

Lung adenocarcinoma (LUAD) is a major health challenge worldwide with an undesirable prognosis. LINC00982 has been implicated as a tumor suppressor in diverse human cancers; however, its role in LUAD has not been fully characterized. Expression level and prognostic value of LINC00982 were investigated in pan-cancer and lung cancer from The Cancer Genome Atlas (TCGA) project. Differential expression analysis based on the LINC00982 expression level was performed in LUAD followed by gene set enrichment analysis (GSEA) and functional enrichment analyses. The association between LINC00982 expression and tumor immune microenvironment characteristics was evaluated. A potential ceRNA regulatory axis was identified and experimentally validated. We found that LINC00982 expression was downregulated and correlated with poor prognosis in LUAD. Enrichment analyses revealed that LINC00982 could inhibit DNA damage repair and cell proliferation, but enhance tumor metabolic reprogramming. We identified a competing endogenous RNA network involving LINC00982, miR-183-5p, and ATP-binding cassette subfamily A member 8 (ABCA8). Luciferase assays confirmed that miR-183-5p can interact with LINC00982 and ABCA8. Forced miR-183-5p expression reduced LINC00982 transcript levels and suppressed ABCA8 expression. Our findings revealed the LINC00982/miR-183-5p/ABCA8 axis as a potential therapeutic target in LUAD.

Amino Acid Metabolism-Regulated Nanomedicine for Enhanced Tumor Immunotherapy through Synergistic Regulation of Immune Microenvironment.

The reprogramming of tumor metabolism presents a substantial challenge for effective immunotherapy, playing a crucial role in developing an immunosuppressive microenvironment. In particular, the degradation of the amino acid L-tryptophan (Trp) to kynurenine (Kyn) by indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) is one of the most clinically validated pathways for immune suppression. Thus, regulating the Trp/Kyn metabolism by IDO1 inhibition represents a promising strategy for enhancing immunotherapy. Herein, metabolism-regulated nanoparticles are prepared through metal coordination-driven assembly of an IDO1 inhibitor (NLG919) and a stimulator of interferon genes (STING) agonist (MSA-2) for enhanced immunotherapy. After intravenous administration, the assembled nanoparticles could efficiently accumulate in tumors, enhancing the bioavailability of NLG919 and down-regulating the metabolism of Trp to Kyn to remodel the immunosuppressive tumor microenvironment. Meanwhile, the released MSA-2 evoked potent STING pathway activation in tumors, triggering an effective immune response. The antitumor immunity induced by nanoparticles significantly inhibited the development of primary and metastatic tumors, as well as B16 melanoma. Overall, this study provided a novel paradigm for enhancing tumor immunotherapy through synergistic amino acid metabolism and STING pathway activation.

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation

IntroductionLung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear.MethodsFirstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan–Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed.ResultsFirstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis.ConclusionOur study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.

Multi-omics study on the molecular mechanism of anlotinib in regulating tumor metabolism

Anlotinib, an orally administered small molecule inhibitor of receptor tyrosine kinases (RTKs), exerts significant anti-angiogenic and vascular normalization effects. However, the mechanisms underlying its involvement in tumor metabolic reprogramming are still unclear. This study aims to investigate the distribution and expression levels of metabolites within tumors after anlotinib treatment using spatial metabolomics analysis. Subsequently, by integrating the transcriptomics and proteomics analyses, we identified that anlotinib treatment primarily modulated four metabolic pathways, including taurine and hypotaurine metabolism, steroid synthesis, pentose phosphate pathway, and lipid biosynthesis. This regulation significantly influenced the metabolic levels of compounds such as sulfonic acids, cholesterol, inositol phosphate pyrophosphate, and palmitoyl-CoA in the tumor, thereby impacting tumor initiation and progression. This study provides potential metabolic biomarkers for anlotinib treatment in tumors.

Single-cell analysis revealing the metabolic landscape of prostate cancer.

Tumor metabolic reprogramming is a hallmark of cancer development, and targeting metabolic vulnerabilities has been proven to be an effective approach for castration-resistant prostate cancer (CRPC) treatment. Nevertheless, treatment failure inevitably occurs, largely due to cellular heterogeneity, which cannot be deciphered by traditional bulk sequencing techniques. By employing computational pipelines for single-cell RNA sequencing, we demonstrated that epithelial cells within the prostate are more metabolically active and plastic than stromal cells. Moreover, we identified that neuroendocrine (NE) cells tend to have high metabolic rates, which might explain the high demand for nutrients and energy exhibited by neuroendocrine prostate cancer (NEPC), one of the most lethal variants of prostate cancer (PCa). Additionally, we demonstrated through computational and experimental approaches that variation in mitochondrial activity is the greatest contributor to metabolic heterogeneity among both tumor cells and nontumor cells. These results establish a detailed metabolic landscape of PCa, highlight a potential mechanism of disease progression, and emphasize the importance of future studies on tumor heterogeneity and the tumor microenvironment from a metabolic perspective.

High expression of NXPH4 correlates with poor prognosis, metabolic reprogramming, and immune infiltration in colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a prevalent gastrointestinal malignant disease with high mortality rate, and identification of novel prognostic biomarkers and therapeutic targets is urgently needed. Although neurexophilin 4 (NXPH4) has been investigated in several tumors, its role in COAD remains unclear. The aim of this study was to explore the prognostic value and potential functions of NXPH4 in COAD. The expression of NXPH4 in COAD were analyzed using The Cancer Genome Atlas (TCGA) and datasets from the Gene Expression Omnibus (GEO) database. The prognostic value of NXPH4 was determined using Kaplan-Meier analysis and Cox regression analysis. To investigate the possible mechanism underlying the role of NXPH4 in COAD, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were employed. The correlation between NXPH4 expression and immune cell infiltration levels was examined thorough single-sample gene set enrichment analysis (ssGSEA). Furthermore, the competing endogenous RNA (ceRNA) regulatory network that may be involved in NXPH4 in COAD was predicted and constructed through a variety of databases. NXPH4 expression was significantly higher in COAD tissue compared with normal colon tissues. Meanwhile, high expression of NXPH4 was associated with poor prognosis in COAD patients. GO-KEGG and GSEA analyses indicated that NXPH4 was associated with glycolysis and hypoxia pathway, and may promote COAD progression and metastasis by modulating metabolic reprogramming. ssGSEA analysis demonstrated that NXPH4 expression also associated with immune infiltration. Furthermore, we identified various microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) as upstream regulators of NXPH4 in COAD. The present study revealed that high expression of NXPH4 is associated with tumor progression, metabolic reprogramming, and immune infiltration. These findings suggest that NXPH4 could serve as a reliable prognostic biomarker and a promising therapeutic target in COAD.

Pan-cancer analyses reveal genomics and clinical outcome association of the fatty acid oxidation regulators in cancer

BackgroundFatty acid oxidation (FAO) is considered to play a vital part in tumor metabolic reprogramming. But the comprehensive description of FAO dysregulation in tumors has not been unknown. MethodsWe obtained FAO genes, RNA-seq data and clinical information from the Msigdb, TCGA and GTEx databases. We assessed their prognosis value using univariate cox analysis, survival analysis and Kaplan-Meier curve. We determined the function of FAO genes using gene set variation analysis. The correlation analysis was calculated by corrplot R package. Immunotherapy response was assessed through TIDE scores. The protein expression levels of FAO genes were validated using immunohistochemistry (IHC). ResultsThe FAO scores were highest in COAD but lowest in PCPG. FAO scores were significantly associated with the prognosis of some cancers in OS, DSS, DFI and PFI. Besides, gene set variation analysis identified that FAO scores were related to immune-related pathways, and immune infiltration analysis showed FAO scores were positively related to cancer-associated fibroblasts and various immune-related genes. TIDE scores were significantly decreased in ACC, CHOL, ESCA, GBM, LAML, SARC, SKCM and THCA compared with normal samples, while it was significantly increased in BLCA, LUAD, LUSC, PCPG, PRAD and STAD. Besides, most FAO genes were downregulated in pan-cancer compared with normal samples. Moreover, we found copy number variation (CNV) of FAO genes played a positive role in their mRNA expression, while methylation was negative. We determined FAO genes were closely related to some drugs in pan-cancer. ConclusionsFAO score is a novel and promising factor for predicting outcomes.

Abstract 7235: Exosome-mediated delivery of siRNA against NRF2 for treatment of lung cancer

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) activation is the third most common genetic event in lung adenocarcinomas (25%), primarily induced by loss of function mutations in its master regulator, KEAP1. NRF2 is a key modulator of tumor growth and metabolic reprogramming, resulting in resistance to traditional chemotherapeutics. Due to its role in modulating oxidative stress, sustained NRF2 overexpression promotes disease progression, particularly in lung cancer. This study demonstrates the effective knockdown of NRF2 expression by small interfering RNA (siRNA) delivered via a nanoplatform based on bovine colostrum exosomes to lung cancer cells, both in vitro and in vivo, resulting in inhibition of proliferation and disease progression. Bovine colostrum is an abundant source of exosomes. Here we present a novel exosome-polyethyleneimine matrix (EPM) to deliver therapeutic siRNA targeting NRF2 expression (siNRF2). Specific delivery of the EPM to tumors was further enhanced via folic acid (FA) functionalization, targeting folate receptors highly expressed on lung tumor cells. Exosomes were isolated from standardized colostrum powder through rehydration and differential centrifugation, and characterized by size, polydispersity index (pdi) and surface charge by Zetasizer, and the presence of surface protein markers by Western blot. siNRF2 was loaded onto the EPM, and the resultant EPM-siNRF2 complex was harvested by PEG precipitation. Entrapment efficiency was determined using 5’-32P-labeled siRNA as a tracer. The gene knockdown efficiency of EPM-siNRF2 was assessed in lung cancer (A549) cells by Western blot and the therapeutic effect of target knockdown in vitro was confirmed by analyzing the corresponding modulation in downstream targets of NRF2. The anti-tumor effect was then evaluated using both subcutaneous and orthotropic lung tumor models in immunocompromised mice. The EPM exhibited high entrapment efficiency (>90%) of siNRF2 (up to 20 μg) and protected entrapped siRNA from enzymatic degradation upon exposure to RNases. EPM-siNRF2 dose dependently decreased NRF2 expression in A549 lung cancer cells. When formulated with FA-functionalized exosomes, EPM-siNRF2 inhibited subcutaneous and orthotropic lung tumors in mice by over 57% (p<0.01) and 84% (p<0.001), respectively. Mice treated with FA-EPM-siNRF2 showed decreased levels of NRF2 in tumor tissue, but not in the adjacent lung, indicating FA-mediated targeted delivery. This bovine colostrum exosome based EPM technology showcases high efficiency in gene knockdown and lung tumor inhibition, providing a promising nanoplatform for delivering nucleic acid therapeutics to the tumor site. Funding: Supported from the NIH grant R44 CA-221487, 3P Biotechnology Contract and, in part, Agnes Brown Duggan Endowment. Keywords: Bovine colostrum, Exosomes, NRF2, siRNA, Lung cancer. Citation Format: Raghuram Kandimalla, Margaret Wallen, Jeyaprakash Jeyabalan, Disha N. Moholkar, Wendy Spencer, Ramesh C. Gupta, Farrukh Aqil. Exosome-mediated delivery of siRNA against NRF2 for treatment of lung cancer [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 7235.