Cancer & Metabolism最新文献

Background: 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.

Methods: 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.

Results: 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.

Conclusion: Simultaneously targeting the PI3K signaling pathway and exogenous FA uptake could potentially be advantageous for patients with PTEN-loss anti-HER2 resistant breast cancer.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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.

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

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.

Background: Six-transmembrane epithelial antigen of prostate 3 (STEAP3), an essential constituent of the STEAP family protein, plays a notable role in promoting cancer proliferation and metastasis. Despite the importance of the STEAP gene family in tumor progression, the function of STEAP3 in cervical cancer (CC) remains unclear.

Materials and methods: The expression of STEAP3 protein in CC tissues and cell lines was identified using immunohistochemistry. The Reduced Representation Bisulfite Sequencing (RRBS) was used to detect global gene DNA methylation in CC tissues and paracancerous tissues. Cell viability, proliferation, migration, and invasion, were evaluated using the Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), wound repair assay, and transwell assay, respectively. RNA sequencing was applied to explore STEAP3-related signaling pathways. Western blotting was performed to detect the expression of related proteins, including epithelial-mesenchymal transition (EMT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling markers.

Results: Herein, STEAP3 was strongly expressed in CC tissues and associated with poor prognosis. CC samples exhibited lower levels of STEAP3 methylation than normal samples, and the methylation levels of CpG islands in STEAP3 were association with prognosis. In contrast to control group, STEAP3 knockdown suppressed the proliferation and invasion of CC cells and enhanced sensitivity to oxaliplatin. Silencing of STEAP3 led to reduced N-cadherin and vimentin levels and increased E-cadherin expression. RNA sequencing analysis suggested that STEAP3 mediated the activation of the JAK STAT3 signaling pathway. Additionally, inhibition of STEAP3 decreased the phosphorylation of JAK2 and STAT3. Interestingly, colivelin (a STAT3 activator) modified STEAP3-induced cell proliferation, invasion, and expression of related proteins in the EMT and JAK/STAT3 signaling pathway.

Conclusion: STEAP3 was significantly associated with CC progression mediated via the JAK/STAT3 signaling pathway and may serve as an effective therapeutic target.

Heterozygosity for loss-of-function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional SDHx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. In the absence of SDH-loss tumor-derived cell models, the cellular burden of SDH loss and succinate accumulation have been investigated through conditional knockouts of SDH subunits in pre-existing murine or human cell lines with varying degrees of clinical relevance. Here we characterize two available murine SDH-loss cell lines, immortalized adrenally-derived premature chromaffin cells vs. immortalized fibroblasts, at a level of detail beyond that currently reported in the literature and with the intention of laying the foundation for future investigations into adaptive pathways and vulnerabilities in SDH-loss cells. We report different mechanistic and phenotypic manifestations of SDH subunit loss in the presented cellular contexts. These findings highlight similarities and differences in the cellular response to SDH loss between the two cell models. We show that adrenally-derived cells display more severe morphological cellular and mitochondrial alterations, yet are unique in preserving residual Complex I function, perhaps allowing them to better tolerate SDH loss, thus making them a closer model to SDH-loss PPGL relative to fibroblasts.(281 words).

Background: Amino acids are critical to tumor survival. Tumors can acquire amino acids from the surrounding microenvironment, including the serum. Limiting dietary amino acids is suggested to influence their serum levels. Further, a plant-based diet is reported to contain fewer amino acids than an animal-based diet. The extent to which a plant-based diet lowers the serum levels of amino acids in patients with cancer is unclear.

Methods: Patients with metastatic breast cancer (n = 17) were enrolled in a clinical trial with an ad libitum whole food, plant-based diet for 8 weeks without calorie or portion restriction. Dietary changes by participants were monitored using a three-day food record. Serum was collected from participants at baseline and 8 weeks. Food records and serum were analyzed for metabolic changes.

Results: We found that a whole food, plant-based diet resulted in a lower intake of calories, fat, and amino acids and higher levels of fiber. Additionally, body weight, serum insulin, and IGF were reduced in participants. The diet contained lower levels of essential and non-essential amino acids, except for arginine (glutamine and asparagine were not measured). Importantly, the lowered dietary intake of amino acids translated to reduced serum levels of amino acids in participants (5/9 essential amino acids; 4/11 non-essential amino acids).

Conclusions: These findings provide a tractable approach to limiting amino acid levels in persons with cancer. This data lays a foundation for studying the relationship between amino acids in patients and tumor progression. Further, a whole-food, plant-based diet has the potential to synergize with cancer therapies that exploit metabolic vulnerabilities.

Trial registration: The clinical trial was registered with ClinicalTrials.gov identifier NCT03045289 on 2017-02-07.

Background: The efficacy of tyrosine kinase inhibitors (TKIs) targeting the EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment.

Methods: Our study employed a comprehensive approach to examine the impact of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the adaptivity of lung cancer cells to EGFR TKI therapies. We conducted metabolomics to trace glucose rerouting in response to PFKFB3 inhibition during TKI treatment. Live cell imaging and DCFDA oxidation were used to quantify levels of oxidation stress. Immunocytochemistry and Neutral Comet assay were employed to evaluate DNA integrity in response to therapy-driven oxidative stress.

Results: Our metabolic profiling revealed that PFKFB3 inhibition significantly alters the metabolic profile of TKI-treated cells. It limited glucose utilization in the polyol pathway, glycolysis, and TCA cycle, leading to a depletion of ATP levels. Furthermore, pharmacological inhibition of PFKFB3 overcome TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), thereby exacerbating oxidative stress. Our study also unveiled a novel role of PFKFB3 in DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. Consequently, PFKFB3 inhibition improved the cytotoxicity of EGFR-TKIs by facilitating ROS-dependent cell death.

Conclusions: Our results suggest that PFKFB3 inhibition reduces glucose utilization and DNA damage repair, limiting the adaptivity of the cells to therapy-driven oxidative stress and DNA integrity insults. Inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR TKI therapy before they enter the drug-resistant state. These findings may have potential implications in the development of new therapies for drug-resistant cancer treatment.