Cancer & Metabolism最新文献

{"title":"Serine starvation suppresses the progression of esophageal cancer by regulating the synthesis of purine nucleotides and NADPH.","authors":"Hui Jie, Jing Wei, Zhuoling Li, Min Yi, Xinying Qian, Yan Li, Chunqi Liu, Chuan Li, Liang Wang, Pengchi Deng, Lunxu Liu, Xiaobo Cen, Yinglan Zhao","doi":"10.1186/s40170-025-00376-4","DOIUrl":"10.1186/s40170-025-00376-4","url":null,"abstract":"<p><p>Serine metabolism provides important metabolic intermediates that support the rapid proliferation of tumor cells. However, the role of serine metabolism in esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remains unclear. Here, we show that serine starvation predominantly inhibits ESCC cell proliferation by suppressing purine nucleotides and NADPH synthesis. Mechanistically, serine depletion led to the accumulation of aminoimidazole carboxamide ribonucleoside (AICAR), an intermediate metabolite of de novo purine synthesis, and AMP/ATP ratio. These increases activated 5'-AMP-activated kinase (AMPK), which subsequently inhibited the mTORC1 pathway by phosphorylating Raptor at Ser792. Moreover, serine depletion decreased NADPH level followed by elevated reactive oxygen species (ROS) production and DNA damage, which induced p53-p21 mediated G1 phase cell cycle arrest. Conversely, serine starvation activated transcription factor 4 (ATF4)-mediated robust expression of phosphoserine aminotransferase 1 (PSAT1) which in turn promoted compensatory endogenous serine synthesis, thus maintaining ESCC cell survival under serine-limited conditions. Accordingly, serine deprivation combined with PSAT1 inhibition significantly suppressed ESCC tumor growth both in vitro and in vivo. Taken together, our findings demonstrate that serine starvation suppresses the proliferation of ESCC cells by disturbing the synthesis of purine nucleotides and NADPH, and the combination of serine deprivation and PSAT1 inhibition significantly impairs ESCC tumor growth. Our study provides a theoretical basis for targeting serine metabolism as a potential therapeutic strategy for ESCC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"10"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate metabolism in clonal plasma cells and its therapeutic implications in multiple myeloma patients with elevated serum LDH levels.","authors":"Yogesh Chawla, Emilie I Anderson, Matthew Smith, Sonia Jain, Laura A Evans, Jadee Neff, Jin Sung Jang, Isas K Vazquez Rosario, Dragan Jevremovic, Xuan-Mai Petterson, Sinto Sebastian, Rafael Fonseca, Shaji K Kumar, Taro Hitosugi, Wilson I Gonsalves","doi":"10.1186/s40170-025-00379-1","DOIUrl":"10.1186/s40170-025-00379-1","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to evaluate the metabolic differences between MM cells derived from patients with elevated serum LDH levels and those without elevated serum LDH levels to identify biological differences that could be exploited for therapeutic purposes.</p><p><strong>Methods: </strong>We performed transcriptome assessments of CD138 + MM cells derived from patients with elevated serum LDH levels compared to those without elevated serum LDH levels and validated the findings in a larger public dataset. Functional metabolic assessments of our findings were performed using a combination of stable isotope resolved metabolomics (SIRM), bioenergetic flux measurement assays, and live cell analysis in human myeloma cell lines and primary MM patient cells.</p><p><strong>Results: </strong>We identified SLC16A1, responsible for the formation of MCT1, a well-defined bi-directional transporter of lactate in and out of a cell with a predilection to importing extracellular lactate, as differentially expressed between the two groups. This finding was functionally confirmed by higher membranous MCT1 protein expression and SIRM on MM cells derived from patients with elevated serum LDH levels compared to those without elevated serum LDH levels. Finally, disrupting lactate transport in and out of CD138 + MM cells was maximally achievable only with dual inhibition of MCT1 and its partner, MCT4, which was preferentially more cytotoxic in MM cells derived from patients with elevated serum levels of LDH.</p><p><strong>Conclusion: </strong>MCT1 mRNA and protein expression distinguish MM cells derived from patients with elevated serum LDH levels from those without elevated serum LDH levels. However, only dual inhibition of MCT1 and MCT4 can disrupt lactate transport in multiple myeloma (MM) cells, with preferential cytotoxicity in MM cells from patients with high serum LDH levels.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"9"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carboxylesterase 1-mediated endocannabinoid metabolism in skin: role in melanoma progression in BRaf^V600E/Pten^-/- mice.","authors":"Veronika Morozova, Daniele Pellegata, Roch-Philippe Charles, Jürg Gertsch","doi":"10.1186/s40170-025-00378-2","DOIUrl":"10.1186/s40170-025-00378-2","url":null,"abstract":"<p><strong>Background: </strong>Melanoma is a highly aggressive skin cancer with a poor prognosis. The endocannabinoids 2-arachidonoylgylcerol (2-AG) and anandamide have been linked to melanoma progression, though their roles remain unclear. We hypothesized that the 2-AG-arachidonate-prostaglandin axis could drive aggressive melanoma progression.</p><p><strong>Methods: </strong>The genetically engineered melanoma mouse model B6-Tyr::CreER^T2; BRaf^CA; Pten^loxP was characterized by targeted metabolomics. Functionally expressed serine hydrolases in the tumor tissue were identified by chemoproteomics. Pharmacological inhibition of carboxylesterase 1 (CES1) was achieved through chronic in vivo i.p. treatment with JZL184 (10 mg/kg daily), confirmed by activity-based protein profiling (ABPP) and targeted lipidomics. CES1-mediated 2-AG hydrolysis was further confirmed in radiotracer-based assays using CES1-transfected cell lines.</p><p><strong>Results: </strong>The diacylglycerol and protein kinase C activator 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) was significantly elevated in the nodular-like melanoma tissues, along with 2-AG and arachidonic acid (ARA), compared to normal skin. AEA and other N-acylethanolamines were decreased, while, notably, prostaglandin levels remained unchanged. Significant changes in the levels of neuromodulators and neurotransmitters, including serotonin and adenosine, were observed. Pronounced differences between serine hydrolase activity in normal skin and melanoma tissue were identified by ABPP. Intriguingly, CES1 was identified as the only 2-AG-hydrolyzing enzyme in this melanoma tissue, as MAGL and ABHD6/12 were not expressed. The MAGL inhibitor JZL184 also efficiently inhibited CES1 in vitro and in vivo, increasing glycerol esters and reducing tumor progression. Additionally, scRNA-seq data from previous studies revealed divergent MAGL/CES1 expression patterns across different human melanoma subtypes.</p><p><strong>Conclusions: </strong>A role of CES1 expression in skin is demonstrated for the first time. Our study suggests that 2-AG degradation to arachidonate favors melanoma progression, either reflecting the carcinogenic role of ARA or that monoacylglycerols like 2-AG and/or other CES1 substrates may exert antitumor effects, indicating that CES1 could be a potential therapeutic target. CES1 expression and high SAG, 2-AG, and ARA levels may be a signature of specific BRAF-driven malignant melanoma subtypes which are associated with discrete metabolic adaptations.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"8"},"PeriodicalIF":6.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma.","authors":"Tung-Wei Hsu, Wan-Yu Wang, Hsin-An Chen, Tzu-Hsuan Wang, Chih-Ming Su, Po-Hsiang Liao, Alvin Chen, Kuei-Yen Tsai, George Kokotos, Cheng-Chin Kuo, Ching-Feng Chiu, Yen-Hao Su","doi":"10.1186/s40170-025-00377-3","DOIUrl":"10.1186/s40170-025-00377-3","url":null,"abstract":"<p><strong>Background: </strong>Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC.</p><p><strong>Methods: </strong>We investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine-resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine-resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259.</p><p><strong>Results: </strong>We observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3'untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer.</p><p><strong>Conclusion: </strong>Our results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"7"},"PeriodicalIF":6.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells.","authors":"You-Yu Liu, Wei-Lun Huang, Sin-Tian Wang, Hui-Ping Hsu, Tzu-Ching Kao, Wei-Pang Chung, Kung-Chia Young","doi":"10.1186/s40170-025-00375-5","DOIUrl":"10.1186/s40170-025-00375-5","url":null,"abstract":"<p><strong>Background: </strong>HER2-positive patients comprise approximately 20% of breast cancer cases, with HER2-targeted therapy significantly improving progression-free and overall survival. However, subsequent reprogramed tumor progression due to PI3K signaling pathway activation by PIK3CA mutations and/or PTEN-loss cause anti-HER2 resistance. Previously, alpha isoform-specific PI3K inhibitors were shown to potentiate HER2-targeted therapy in breast cancer cells carrying PI3K pathway alterations with less potent effects on PTEN-loss than PIK3CA-mutant cells. Therefore, seeking for alternative combination therapy needs urgent attentions in PTEN-loss anti-HER2 resistant breast cancer.</p><p><strong>Methods: </strong>Since remodeling of fatty acid (FA) metabolism might contribute to HER-positive breast cancer and is triggered by the PI3K signal pathway, herein, we examined the effects of the inhibition of endogenous FA conversion, SCD-1 or exogenous FA transport, CD36, in combination with PI3K inhibitors (alpelisib and inavolisib) in anti-HER2 resistant PTEN-loss breast cancer cells.</p><p><strong>Results: </strong>The activated HER2/PI3K/AKT/mTOR signaling pathway positively correlated with SCD-1 and CD36 expression in PTEN-loss breast cancer cells. PI3K inhibition downregulated SCD-1, and accordingly, the addition of the SCD-1 inhibitor did not augment the antiproliferative effects of the PI3K inhibitors. CD36 was upregulated by blocking the PI3K signal pathway or limited serum supplementation, indicating that suppressing CD36 may decrease the excess transport of exogenous FA. The addition of the CD36 inhibitor synergistically enhanced the anti-proliferative effects of the PI3K inhibitors.</p><p><strong>Conclusion: </strong>Simultaneously targeting the PI3K signaling pathway and exogenous FA uptake could potentially be advantageous for patients with PTEN-loss anti-HER2 resistant breast cancer.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"6"},"PeriodicalIF":6.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steatohepatitis-induced vascular niche alterations promote melanoma metastasis.","authors":"Johannes Hoffmann, Julia Schüler, Bianca Dietsch, Sina Wietje Kürschner-Zacharias, Carsten Sticht, Felix A Trogisch, Maren Schreitmüller, Tinja Baljkas, Kai Schledzewski, Manuel Reinhart, Sebastian A Wohlfeil, Manuel Winkler, Christian David Schmid, Joerg Heineke, Cyrill Géraud, Sergij Goerdt, Philipp-Sebastian Reiners-Koch, Victor Olsavszky","doi":"10.1186/s40170-025-00374-6","DOIUrl":"10.1186/s40170-025-00374-6","url":null,"abstract":"<p><strong>Background: </strong>In malignant melanoma, liver metastases significantly reduce survival, even despite highly effective new therapies. Given the increase in metabolic liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), this study investigated the impact of liver sinusoidal endothelial cell (LSEC)-specific alterations in MASLD/MASH on hepatic melanoma metastasis.</p><p><strong>Methods: </strong>Mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for ten weeks to induce MASH-associated liver fibrosis, or a CDAA diet or a high fat diet (HFD) for shorter periods of time to induce early steatosis-associated alterations. Liver metastasis formation was assessed using melanoma cell lines B16F10Luc2 and Wt31. LSEC-specific GATA4 knockout mice (Gata4^LSEC-KO/BL) developing MASH-like liver fibrosis without steatosis via a pathogenic angiocrine switch were included to compare the impact of liver fibrosis versus hepatic steatosis on hepatic melanoma metastasis. Bulk RNA-Seq of isolated LSECs from CDAA-fed and control mice was performed. Levels of adhesion molecules (VCAM1, ICAM1, E-selectin) were monitored, and ICAM1 and VCAM1 antibody therapy was employed.</p><p><strong>Results: </strong>Feeding a CDAA diet, in contrast to a HFD, led to increased metastasis before the development of liver fibrosis. Gata4^LSEC-KO/BL mice characterized by vascular changes ensuing perisinusoidal liver fibrosis without steatosis also exhibited increased metastasis. Early molecular alterations in the hepatic vascular niche, rather than fibrosis or steatosis, correlated with metastasis, as shown by LSEC dedifferentiation and upregulation of endothelial adhesion molecules. The metastatic process in CDAA-fed mice was also dependent on the respective melanoma cell lines used and on the route of their metastatic spread. ICAM1 inhibition, but not VCAM1 inhibition reduced melanoma cell retention.</p><p><strong>Conclusion: </strong>We discovered that the hepatic vascular niche acts as a delicate sensor to even short-term nutritional alterations during the development of MASLD/MASH. The dynamic adaptations to the metabolic challenges of developing MASLD/MASH caused an early shift from the normal hepatic vascular niche to a pre-metastatic vascular niche that promoted hepatic melanoma metastasis in the context of cell-autonomous and acquired melanoma cell features. Altogether, our findings provide a potential avenue for angiotargeted therapies to prevent hepatic melanoma metastasis.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"5"},"PeriodicalIF":6.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response.","authors":"Ceren Yalaz, Esther Bridges, Nasullah K Alham, Christos E Zois, Jianzhou Chen, Karim Bensaad, Ana Miar, Elisabete Pires, Ruth J Muschel, James S O McCullagh, Adrian L Harris","doi":"10.1186/s40170-024-00371-1","DOIUrl":"10.1186/s40170-024-00371-1","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"4"},"PeriodicalIF":6.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GDF15-mediated enhancement of the Warburg effect sustains multiple myeloma growth via TGFβ signaling pathway.","authors":"Wenjing Xue, Ying Li, Yanna Ma, Feng Zhang","doi":"10.1186/s40170-025-00373-7","DOIUrl":"10.1186/s40170-025-00373-7","url":null,"abstract":"<p><p>The Warburg effect, characterized by the shift toward aerobic glycolysis, is closely associated with the onset and advancement of tumors, including multiple myeloma (MM). Nevertheless, the specific regulatory mechanisms of glycolysis in MM and its functional role remain unclear. In this study, we identified that growth differentiation factor 15 (GDF15) is a glycolytic regulator, and GDF15 is highly expressed in MM cells and patient samples. Through gain-of-function and loss-of-function experiments, we demonstrated that GDF15 promotes MM cell proliferation and inhibits apoptosis. Moreover, GDF15 enhances Warburg-like metabolism in MM cells, as evidenced by increased glucose uptake, lactate production, and extracellular acidification rate, while reducing oxidative phosphorylation. Importantly, the tumor-promoting effects of GDF15 in MM cells are fermentation-dependent. Mechanistically, GDF15 was found to promote the expression of key glycolytic genes, particularly the glucose transporter GLUT1, through the activation of the TGFβ signaling pathway. Pharmacological inhibition of the TGFβ signaling pathway effectively abrogated the oncogenic activities of GDF15 in MM cells, including cell proliferation, apoptosis, and fermentation. In vivo experiments using a subcutaneous xenotransplanted tumor model confirmed that GDF15 knockdown led to a significant reduction in tumor growth, while GDF15 overexpression promoted tumor growth. Overall, our study provides insights into the molecular mechanisms underlying MM pathogenesis and highlights the potential of targeting GDF15-TGFβ signaling -glycolysis axis as a therapeutic approach for future therapeutic interventions in MM.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"3"},"PeriodicalIF":6.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploratory profiling of metabolites in cerebrospinal fluid using a commercially available targeted LC-MS based metabolomics kit to discriminate leptomeningeal metastasis.","authors":"Soojin Jang, Ho-Shin Gwak, Kyue-Yim Lee, Jun Hwa Lee, Kyung-Hee Kim, Jong Heon Kim, Jong Bae Park, Sang Hoon Shin, Heon Yoo, Yun-Sik Dho, Kyu-Chang Wang, Byong Chul Yoo","doi":"10.1186/s40170-024-00367-x","DOIUrl":"10.1186/s40170-024-00367-x","url":null,"abstract":"<p><strong>Background: </strong>Leptomeningeal metastasis (LM) is a devastating complication of cancer that is difficult to treat. Thus, early diagnosis is essential for LM patients. However, cerebrospinal fluid (CSF) cytology has low sensitivity, and imaging approaches are ineffective. We explored targeted CSF metabolic profiling to discriminate among LM and other conditions affecting the central nervous system (CNS).</p><p><strong>Methods: </strong>We quantitatively measured amino acids, biogenic amines, hexoses, acylcarnitines (AC), cholesteryl esters (CE), glycerides, phosphatidylcholines (PC), lysophosphatidylcholines (LPC), sphingomyelins (SM), and ceramides (Cer) in 117 CSF samples from various groups of healthy controls (HC, n = 10), patients with LM (LM, n = 47), parenchymal brain tumor (PBT, n = 45), and inflammatory disease (ID, n = 13) with internal standards using the Absolute IDQ- p400^® targeted mass spectrometry kit. Metabolites detected in > 90% of samples or showing a difference in proportional level between groups ≥ 75% were used in logistic regression models when there was no single metabolite with AUC = 1 for the groups of comparison.</p><p><strong>Results: </strong>PC and SM had higher levels in LM than in PBT or HC, whereas LPC had lower level in PBT than the other groups. Glycerides and Cer levels were higher in PBT and LM than in HC. Long-chain AC level in PBT was lower than in LM or HC. A regression model including Ala, PC (42:7), PC (30:3), PC (37:0), and Tyr achieved complete discrimination (AUC = 1.0) between LM and HC. In comparison of PBT and HC, twenty-six individual metabolites allowed complete discrimination between two groups, and between ID and HC fourty-six individual lipid metabolites allowed complete discrimination. Twenty-one individual metabolites (18 ACs and 3 PCs) allowed complete discrimination between LM and PBT.</p><p><strong>Conclusions: </strong>Using a commercial targeted liquid chromatography-mass spectrometry (LC-MS) metabolomics kit, we were able to differentiate LM from HC and PBT. Most of the discriminative metabolites among different diseases were lipid metabolites, for which their CNS distribution and quantification in different cell types are largely unknown, whereas amino acids, biogenic amines, and hexoses failed to show significant differences. Future validation studies with larger, controlled cohorts should be performed, and hopefully, the kit may expand its metabolite coverage for unique cancer cell glucose metabolism.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"2"},"PeriodicalIF":6.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphatidylinositol promoted the proliferation and invasion of pituitary adenoma cells by regulating POU1F1 expression.","authors":"Tongjiang Xu, Xiaodong Zhai, RuiWei Wang, Xiaoben Wu, ZhiZhen Zhou, MiaoMiao Shang, Chongcheng Wang, Tengfei Qi, Wei Yang","doi":"10.1186/s40170-024-00372-0","DOIUrl":"10.1186/s40170-024-00372-0","url":null,"abstract":"<p><p>Invasiveness of pituitary adenoma is the main cause of its poor prognosis, mechanism of which remains largely unknown. In this study, the differential proteins between invasive and non-invasive pituitary tumors (IPA and NIPA) were identified by TMT labeled quantitative proteomics. The differential metabolites in venous bloods from patients with IPA and NIPA were analyzed by untargeted metabolomics. Proteomic data showed that the top five up-regulated proteins were AD021, C2orf15, PLCXD3, HIST3H2BB and POU1F1, and the top five down-regulated proteins were AIPL1, CALB2, GLUD2, SLC4A10 and GTF2I. Metabolomic data showed that phosphatidylinositol (PI) was most remarkably up-regulated and melibiose was most obviously down-regulated. Further investigation demonstrated that PI stimulation increased the expression of PITPNM1, POU1F1, C2orf15 and LDHA as well as the phosphorylation of AKT and ERK, and promoted the proliferation, migration and invasion of GH3 cells, which were blocked by PITPNM1knockdown. Inhibiting AKT phosphorylation reduced the expression of POU1F1, C2orf15 and LDHA in PI-stimulated cells while activating AKT increased their expression in PITPNM1-silencing cells, which was similar to the function of ERK. POU1F1 silence suppressed the expression of LDHA and C2orf15. Luciferase report assay and ChIP assay demonstrated that POU1F1 positively regulated the transcription of LDHA and C2orf15. In addition, PI propelled the metastasis of GH3 cells in vivo, and elevated the expression of PITPNM1, POU1F1, C2orf15 and LDHA. These results suggested that elevated serum PI might contribute to the proliferation and invasion of pituitary adenoma by regulating the expression of PITPNM1/AKT/ERK/POU1F1 axis.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"1"},"PeriodicalIF":6.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}