Cancer & Metabolism最新文献

Breast cancer remains the most prevalent malignancy among women globally, with its complexity linked to genetic variations and metabolic alterations within tumor cells. This study investigates the role of fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, in breast cancer progression. Our findings reveal that FH mRNA and protein levels are significantly upregulated in breast cancer tissues and correlate with poor patient prognosis and aggressive tumor characteristics. Using in vitro and in vivo models, we demonstrate that FH overexpression enhances breast cancer cell proliferation, migration, and invasion through metabolic reprogramming and by increasing reactive oxygen species (ROS) production. Furthermore, we identify matrix metalloproteinase 1 (MMP1) as a downstream effector of FH, linked to p21 downregulation, elucidating a novel regulatory pathway influencing tumor behavior. Interestingly, unlike its tumor-suppressing role in other cancer types, this study highlights FH's oncogenic potential in breast cancer. Our results suggest that FH enhances cancer cell viability and aggressiveness via both catalytic and non-catalytic mechanisms. This work not only underscores the metabolic adaptations of breast cancer cells but also proposes FH as a potential biomarker and therapeutic target for breast cancer management.

Increasing emphasis has been placed on improving the physiological relevance of cell culture media with formulations such as Human Plasma-Like Medium (HPLM). Given that shifts in mitochondrial metabolism and nutrient use are emerging as anti-cancer targets, the present study sought to investigate the impact of culture media formulation on mitochondrial bioenergetics and cancer cell growth. To do this, we used acute myeloid leukemia (AML) cells and compared acute and chronic effects of HPLM versus different supraphysiological medias. The AML mitochondrial phenotype was largely unaffected by exposure to either physiological or supraphysiological medias, establishing that the key features of AML mitochondria remain phenotypically stable under diverse nutrient conditions and proliferation rates. Both acute and chronic culturing in HPLM slowed AML cell proliferation. However, merely identifying and supplementing single nutrients that were deficient in HPLM did not improve proliferation and was not sufficient to pinpoint actionable fuel preferences. Transferring cells back to native Iscove's Modified Dulbecco's Medium (IMDM) media immediately restored the proliferative phenotype, suggesting responsiveness to the entirety of the nutrient environment. Supraphysiological culture medias other than IMDM were all characterized by slower proliferation; however, none were associated with changes in cell viability, demonstrating that the native culture medium is optimal if the experimental aim is maximal growth. Despite Dulbecco's Modified Eagle Medium (DMEM) being similar in nutrient composition to IMDM and categorized as supraphysiological, both acute and chronic culturing in DMEM resulted in slower growth, akin to what was observed with HPLM. Altogether, independent of growth, AML mitochondria remain largely unperturbed by changes in the culture media, and rather than specific nutrients or physiological relevance, AML cell proliferation is influenced by the complete nutrient profile.

Background: The tumor microenvironment (TME) supplies critical metabolites that support cancer cell survival and progression. Adipocytes support tumor progression by secreting free fatty acids (FFAs) and adipokines; however, the role and mechanisms underlying lipid droplet (LD) release from adipocytes remain elusive.

Methods: Using two nasopharyngeal carcinoma (NPC) cell lines and primary human pre-adipocytes (HPA), we evaluate the effect of LDs on cell growth, proliferation, colony formation, and migration. We also assess the roles of LD on the tumor progression in vivo. Using RNA-seq analysis, we elucidate the effect of hypoxic NPC cell-derived exosomes (H-exo) on the gene expression profile of adipocytes. By co-culture system, we investigated the effect of vacuolar protein sorting 4 homolog B (VPS4B)-annexin A5 (ANXA5) interaction on adipocyte LD maturity and release.

Results: Herein, we report that LDs, rather than FFAs, are the primary lipid form transferred from adipocytes to NPC cells, enhancing cancer progression. NPC cells internalize LDs directly via macropinocytosis, while H-exo induces oxidative stress and membrane fluidity in adipocytes, leading to LD release. Transcriptomic and proteomic analyses reveal that VPS4B triggers LD release by interacting with ANXA5, and low LKB1 in H-exo enhances VPS4B O-linked N-acetylglucosamine (O-GlcNAc) modification through the inhibition of serine/threonine kinase 11 (STK11/LKB1)-AMP-activated protein kinase (AMPK) pathway and activation of the hexosamine biosynthesis pathway (HBP) flux.

Conclusions: This study uncovers critical mechanisms of LD transfer in the TME, suggesting new therapeutic avenues in NPC.

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).