Cancer & Metabolism最新文献

Background: Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD⁺.

Methods: We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry.

Results: Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD⁺ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD⁺/NADH ratio in AML cells. Continuous intracellular NAD⁺ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition.

Conclusions: Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD⁺/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD⁺ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.

Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8⁺ T cells. Instead, cancer cells outcompete CD8⁺ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8⁺ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.

Background: Malignant ascites is a common complication of advanced ovarian cancer (OC) and gastrointestinal cancer (GI), significantly impacting metastasis, quality of life, and survival. Increased intestinal permeability can lead to blood or lymphatic infiltration and microbial translocation from the gastrointestinal or uterine tract. This study aimed to identify microbiota-derived metabolites in ascites from OC (stages II-III and IV) and GI patients, assessing their roles in tumor progression.

Methods: Malignant ascites samples from 18 OC and GI patients were analyzed using a four-dimensional (4D) untargeted metabolomics approach combining reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC) with trapped ion mobility spectrometry time-of-flight mass spectrometry (timsTOF-MS). Additonally, a targeted flow cytometry-based cytokine panel was used to screen for inflammatory markers. Non-endogenous, microbiota-derived metabolites were identified through the Human Microbial Metabolome Database (MiMeDB).

Results: OC stage IV exhibited metabolic profiles similar to GI cancers, while OC stage II-III differed significantly. Stage IV OC patients exhibited higher levels of 11 typically microbiome-derived metabolites, including 1-methylhistidine, 3-hydroxyanthranilic acid, 4-pyridoxic acid, biliverdin, butyryl-L-carnitine, hydroxypropionic acid, indole, lysophosphatidylinositol 18:1 (LPI 18:1), mevalonic acid, N-acetyl-L-phenylalanine, and nudifloramide, and lower levels of 5 metabolites, including benzyl alcohol, naringenin, o-cresol, octadecanedioic acid, and phenol, compared to stage II-III. Correlation analysis revealed positive associations between IL-10 and metabolites such as glucosamine and LPCs, while MCP-1 positively correlated with benzyl alcohol and phenol.

Conclusion: 4D metabolomics revealed distinct metabolic signatures in OC and GI ascites, highlighting microbiota-derived metabolites involved in lipid metabolism and inflammation. Metabolites like 3-hydroxyanthranilic acid, indole, and naringenin may serve as markers of disease progression and underscore the microbiota's role in shaping malignant ascites and tumor biology.

Estrogen receptor (ER)-positive breast cancer (BC) is a prevalent and fatal cancer among women, and there is a need to identify molecules involved in the disease pathophysiology which could also serve as biomarkers for early detection. Detection of cancer markers in whole plasma produces excessive information, and identifying important markers involved in cancer progression is challenging. We identified a BC-specific low-density lipoprotein (LDL) particle isolated by ultracentrifugation from the plasma of ER-positive BC patients. This LDL has an aberrant proteome and lipidome, significantly different from that of LDL from healthy women, including a high association with the pro-tumor chemokines CXCL4 and CXCL7, and an enrichment with the lipid subclasses phosphatidylethanolamine, ceramide, triglycerides, lysophosphatidylcholine, phosphatidylserine, phosphatidic acid, and sphingomyelin. In contrast, phosphatidylinositol species were significantly less abundant in LDL from tumor patients than in control. Moreover, BC-associated LDL has a distinct effect on macrophage phenotype, inducing an increased gene expression of IL1β, IL8 and CD206 and decreased gene expression of TNFα, a gene signature characteristic of tumor-associated macrophages (TAMs). This suggests that this formerly unrecognized form of LDL may represent LDL particles that are recruited by the tumor microenvironment to support tumor progression by inducing discrete subsets of TAMs. In conclusion, these data offer BC-associated LDL as an early biomarker detection platform for ER-positive BC. Furthermore, LDL-associated proteins and lipids that promote BC progression may also serve in the future as novel targets for BC therapies.

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatocellular cancer. This study investigated whether ETV4, ALYREF, and PKM2 affect glycolytic metabolism and ferroptosis, thereby potentially influencing ICC.

Methods: Bioinformatic analysis was used to explore the expression levels and prognosis of ETV4, ALYREF, and PKM2 in ICC and their regulatory relationships were confirmed using in vitro experiments. Glycolytic metabolism and ferroptosis were examined, and chromatin immunoprecipitation and RNA immunoprecipitation experiments were performed to verify whether the ETV4, PKM2, and ALYREF could bind. The effect of ETV4/ALYREF on ICC was further confirmed by in vivo experiments.

Results: ETV4, ALYREF, and PKM2 were highly expressed in ICC. Overexpressed (oe)-ETV4 and oe-PKM2 promoted cell migration and increased glucose (GLU) utilization and lactate and intracellular adenosine triphosphate (ATP) production. Addition of the ferroptosis inducer Erastin to the above groups revealed that sh-ETV4 and sh-ALYREF increased lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe²⁺ levels, and oe-PKM2 reversed these effects in the sh-ETV4 and sh-ALYREF groups. Oe-ETV4 promoted the expression of PKM2, whereas sh-ALYREF inhibited the same. ETV4 could bind to ALYREF and PKM2 promoter, and ALYREF could promote the stability of PKM2 in an m5C-dependent manner. In vivo, ETV4 promotes tumor growth and the expression of proteins related to glycolytic metabolism by regulating ALYREF.

Conclusion: ETV4 promotes ICC development and ferroptosis resistance by facilitating glycolytic metabolism, and regulating PKM2 transcription by directly binding to the PKM2 promoter. Additionally, it mediates m5C-dependent PKM2 stabilization by directly binding to ALYREF. This study identified a new potential therapeutic target for ICC.

Background: While the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown, recent evidence suggests that intrinsic cellular metabolism could be a crucial driver of migratory disposition and chemoresistance. Aiming to decipher the molecular mechanisms involved in BC cell metabolic maneuvering, we study how a ketomimetic (ketone body-rich, low glucose) nutrient medium can engineer the glycocalyx and metabolic signature of BC cells, to further maneuver their response to therapy.

Methods: Doxorubicin (DOX) has been used as a model chemotherapeutic in this study. Bioorthogonal imaging was used to assess the degree of sialylation of the glycocalyx along with measurements of drug-induced cytotoxicity and drug internalization. Single cell label-free metabolic imaging has been performed, coupled with measurement of cellular proliferative and migratory abilities, and MS-based metabolomic screens. Transcriptomic analysis of crucial enzymes was performed using total RNA extraction and rt-qPCR.

Results: We found an inverse correlation of glycocalyx sialylation with drug-induced cytotoxicity and drug internalization, where ketomimetic media enhanced sialylation and protected BC cells from DOX. These hypersialylated cells proliferated slower and migrated faster as compared to their counterparts receiving a high glucose media, while exhibiting a preference for glycolysis. These cells also showed pronounced lipid droplet accumulation coupled with an inversion in their metabolomic profile. Enzymatic removal of sialic acid moieties at the glycocalyx revealed for the first time, a direct role of sialic acids as defense guards, blocking DOX entry at the cellular membrane to curtail internalization. Interestingly, the non-cancerous mammary epithelial cells exhibited opposite trends and this differential pattern in cancer vs. normal cells was traced to its biochemical roots, i.e. the expression levels of key enzymes involved in sialylation and fatty acid synthesis.

Conclusions: Our findings revealed that a ketomimetic medium enhances chemoresistance and invasive disposition of BC cells via two main oncogenic pathways: hypersialylation and lipid synthesis. We propose that the crosstalk between these pathways, juxtaposed at the synthesis of the glycan precursor UDP-GlcNAc, furthers advancement of a metastatic phenotype in BC cells under ketomimetic conditions. Non-cancerous cells lack this dual defense machinery and end up being sensitized to DOX under ketomimetic conditions.

Background: Endometrial cancer (EC) is one of the most common cancers in women, with a short overall survival and poor prognosis. Besides the biologically aggressive EC properties, Cancer-associated cachexia is the main factor. However, the detailed mechanism underlying EC-related cachexia and its harmful effects on EC progression and patient prognosis remains unclear.

Methods: For clinical specimen and the vitro experiment, we detected TRIM22 expression level, EC patients' survival time, EC cell functional change, and adipose thermogenic changes to identify the function of TRIM22 in EC progression, EC-associated cachexia, and their molecular mechanisms. Then, for the vivo experiment, we exploited the xenografts in mice to identify the function of TRIM22 again, and to screen the drug therapeutic schedule.

Results: Herein, we demonstrated that TRIM22 inhibited EC cell growth, invasion, and migration. Interleukin (IL)-6 mediated brown adipose tissue activation and white adipose tissue browning which induced EC-related cachexia. TRIM22 suppressed the EC cells' secretion of IL-6, and IL-6 mediated EC-related cachexia. Mechanistically, TRIM22 inhibited EC progression by suppressing the nucleotide-binding oligomerization domain 2(NOD2)/nuclear factor-kappaB (NF-κB) signaling pathway, with the purpose of impeding the production of IL-6. Moreover, we revealed that TRIM22 inhibited EC-associated cachexia by suppressing the IL-6/IL-6 receptor (IL-6R) signaling pathway. Therapeutically, we demonstrated that combination treatment with a TRIM22 inducer (progesterone) and a thermogenic inhibitor (IL-6R antibody) synergistically augmented the antitumor efficacy of carbotaxol (carboplatin and paclitaxel), in vivo.

Conclusion: Our data reveals that TRIM22-EC-IL-6-cachexia cross-communication has important clinical relevance and that the use of combined therapy holds great promise for enhancing the efficacy of anti-ECs. (Fig. graphical abstract).

Background: Small cell lung cancer (SCLC) is an aggressive malignancy with distinct molecular subtypes defined by transcription factors and inflammatory characteristics. This follow-up study aimed to validate the unique metabolic phenotype in achaete-scute homologue 1 (ASCL1)-driven SCLC cell lines and human tumor tissue.

Methods: Metabolic alterations were analyzed using proteomic data. Structural and functional differences of mitochondria were investigated using qPCR, flow cytometry, confocal imaging, and transmission electron microscopy and seahorse assays. Several metabolic inhibitors were tested using MTT-based and clonogenic assays. Single-cell enzyme activity assays were conducted on cell lines and tumor tissue samples of SCLC patients.

Results: We found increased mitochondrial numbers correlating with higher oxidative phosphorylation activity in ASCL1-dominant cells compared to other SCLC subtypes. Metabolic inhibitors targeting mitochondrial respiratory complex-I or carnitine palmitoyltransferase 1 revealed higher responsiveness in SCLC-A. Conversely, we demonstrated that non-ASCL1-driven SCLCs with lower oxidative signatures show dependence on glutaminolysis as evidenced by the enhanced susceptibility to glutaminase inhibition. Accordingly, we detected increased glutamate-dehydrogenase activity in non-ASCL1-dominant cell lines as well as in human SCLC tissue samples.

Conclusions: Distinct SCLC subtypes exhibit unique metabolic vulnerabilities, suggesting potential for subtype-specific therapies targeting the respiratory chain, fatty acid transport, or glutaminolysis.

Background: Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing sepiapterin (SEP), the endogenous precursor of tetrahydrobiopterin (BH_4, the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we tested our hypothesis that a long-term administration of SEP to individuals susceptible to HER2-positive mammary tumor would protect them against tumor occurrence.

Methods: We administered SEP, in comparison to control DMSO, to MMTV-neu mice susceptible to HER2-positive mammary tumors for 8 months starting at their pre-pubertal stage. We monitored tumor onsets to determine the rate of tumor-free survival. After 8 months of treatment, we grouped animals into DMSO treatment with or without tumors and SEP treatment with or without tumors. We analyzed blood metabolites, PBMC, and bone marrow of DMSO vs. SEP treated animals.

Results: We found that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively suppressed tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention.

Conclusions: These findings suggest the possible roles of the SEP/BH₄/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.

High-grade serous cancer (HGSC) is the most prevalent and aggressive subtype of ovarian cancer. In this study, we utilized liquid chromatography and mass spectrometry analysis to investigate metabolic alterations in HGSC. Among the 1353 metabolites identified, 140 were significantly differed between HGSC and normal ovarian tissue. KEGG pathway enrichment analysis revealed 23 distinct metabolic pathways, including the alanine/aspartate/glutamate metabolism, pyruvate metabolism, biosynthesis of amino acids, and citrate cycle, etc. Of the significantly differentiated metabolites, malic acid, fumarate, and phosphoenolpyruvate were found in the citrate cycle and glycolysis. In further analysis, 22 differentially expressed genes (DEGs) of glucose metabolism were found between HGSC and normal controls. Multivariate Cox analysis of the 22 DEGs showed that ME1, ALDOC, and RANBP2 were associated with overall survival in the TCGA cohort.Bioinformatic analysis indicated WTAP is strongly correlated to the expression of ME1, which is a rate-limiting enzyme that regulates the shuttle of malic acid in mitochondria and cytoplasm. After the knockdown of WTAP in A2780 and OVCAR-3 cells, the activity of the malic enzyme decreased which led to the accumulation of malic acid and citric acid, and the reduction of pyruvate and lactic acid. In A2780 and OVCAR-3 cells, the IC50 to platinum was increased after the knockdown of WTAP. After the knockdown of WTAP, the expression of ME1 was down-regulated and the m6A modification was down-regulated in ovarian cell lines. On the SRAMP website, there were two binding sites with high m6A scores at the 5 '-UTR 177 and 970 of ME1 mRNA. WTAP contributes to the platinum resistance through regulating the conversion from aerobic glycolysis to OXPHOS by upregulating the expression of ME1.