Cancer & Metabolism最新文献

{"title":"Scaffold-mediated switching of lymphoma metabolism in culture.","authors":"Rachana Bhatt, Dashnamoorthy Ravi, Andrew M Evens, Biju Parekkadan","doi":"10.1186/s40170-022-00291-y","DOIUrl":"10.1186/s40170-022-00291-y","url":null,"abstract":"<p><strong>Background: </strong>Diffuse large B cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and accounts for about a third of all NHL cases. A significant proportion (~40%) of treated DLBCL patients develop refractory or relapsed disease due to drug resistance which can be attributed to metabolomic and genetic variations amongst diverse DLBCL subtypes. An assay platform that reproduces metabolic patterns of DLBCL in vivo could serve as a useful model for DLBCL.</p><p><strong>Methods: </strong>This report investigated metabolic functions in 2D and 3D cell cultures using parental and drug-resistant DLBCL cell lines as compared to patient biopsy tissue.</p><p><strong>Results: </strong>A 3D culture model controlled the proliferation of parental and drug-resistant DLBCL cell lines, SUDHL-10, SUDHL-10 RR (rituximab resistant), and SUDHL-10 OR (obinutuzumab resistant), as well as retained differential sensitivity to CHOP. The results from metabolic profiling and isotope tracer studies with D-glucose-¹³C₆ indicated metabolic switching in 3D culture when compared with a 2D environment. Analysis of DLBCL patient tumor tissue revealed that the metabolic changes in 3D grown cells were shifted towards that of clinical specimens.</p><p><strong>Conclusion: </strong>3D culture restrained DLBCL cell line growth and modulated metabolic pathways that trend towards the biological characteristics of patient tumors. Counter-intuitively, this research thereby contends that 3D matrices can be a tool to control tumor function towards a slower growing and metabolically dormant state that better reflects in vivo tumor physiology.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"15"},"PeriodicalIF":6.0,"publicationDate":"2022-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9559005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9841008","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":"Metabolic flux analysis of 3D spheroids reveals significant differences in glucose metabolism from matched 2D cultures of colorectal cancer and pancreatic ductal adenocarcinoma cell lines","authors":"Tidwell, Tia R., Røsland, Gro V., Tronstad, Karl Johan, Søreide, Kjetil, Hagland, Hanne R.","doi":"10.1186/s40170-022-00285-w","DOIUrl":"https://doi.org/10.1186/s40170-022-00285-w","url":null,"abstract":"Most in vitro cancer cell experiments have been performed using 2D models. However, 3D spheroid cultures are increasingly favored for being more representative of in vivo tumor conditions. To overcome the translational challenges with 2D cell cultures, 3D systems better model more complex cell-to-cell contact and nutrient levels present in a tumor, improving our understanding of cancer complexity. Despite this need, there are few reports on how 3D cultures differ metabolically from 2D cultures. Well-described cell lines from colorectal cancer (HCT116 and SW948) and pancreatic ductal adenocarcinoma (Panc-1 and MIA-Pa-Ca-2) were used to investigate metabolism in 3D spheroid models. The metabolic variation under normal glucose conditions were investigated comparing 2D and 3D cultures by metabolic flux analysis and expression of key metabolic proteins. We find significant differences in glucose metabolism of 3D cultures compared to 2D cultures, both related to glycolysis and oxidative phosphorylation. Spheroids have higher ATP-linked respiration in standard nutrient conditions and higher non-aerobic ATP production in the absence of supplemented glucose. In addition, ATP-linked respiration is significantly inversely correlated with OCR/ECAR (p = 0.0096). Mitochondrial transport protein, TOMM20, expression decreases in all spheroid models compared to 2D, and monocarboxylate transporter (MCT) expression increases in 3 of the 4 spheroid models. In this study of CRC and PDAC cell lines, we demonstrate that glucose metabolism in 3D spheroids differs significantly from 2D cultures, both in terms of glycolytic and oxidative phosphorylation metrics. The metabolic phenotype shift from 2D to 3D culture in one cell line is greater than the phenotypic differences between each cell line and tumor source. The results herein emphasize the need to use 3D cell models for investigating nutrient utilization and metabolic flux for a better understanding of tumor metabolism and potential metabolic therapeutic targets.","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"34 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2022-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138524874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An iron chelation-based combinatorial anticancer therapy comprising deferoxamine and a lactate excretion inhibitor inhibits the proliferation of cancer cells.","authors":"Koichi Fujisawa,&nbsp;Taro Takami,&nbsp;Toshihiko Matsumoto,&nbsp;Naoki Yamamoto,&nbsp;Takahiro Yamasaki,&nbsp;Isao Sakaida","doi":"10.1186/s40170-022-00284-x","DOIUrl":"https://doi.org/10.1186/s40170-022-00284-x","url":null,"abstract":"<p><strong>Background: </strong>Although iron chelation has garnered attention as a novel therapeutic strategy for cancer, higher levels of efficacy need to be achieved. In the present study, we examined the combinatorial effect of deferoxamine (DFO), an iron chelator, and α-cyano-4-hydroxy cinnamate (CHC), a suppressor of lactate excretion, on the proliferation of cancer cell lines.</p><p><strong>Methods: </strong>We established a deferoxamine (DFO)-resistant cell line by culturing HeLa cells in media containing increasing concentrations of DFO. Metabolome and gene expression analyses were performed on these cells. Synergistic effect of the drugs on the cells was determined using an in vitro proliferation assay, and the combination index was estimated.</p><p><strong>Results: </strong>DFO-resistant HeLa cells exhibited enhanced glycolysis, salvage cycle, and de novo nucleic acid synthesis and reduced mitochondrial metabolism. As DFO triggered a metabolic shift toward glycolysis and increased lactate production in cells, we treated the cancer cell lines with a combination of CHC and DFO. A synergistic effect of DFO and CHC was observed in HeLa cells; however, the same was not observed in the human liver cancer cell line Huh7. We hypothesized that the efficacy of the combination therapy in cancer cells depends on the degree of increase in lactate concentration upon DFO treatment.</p><p><strong>Conclusion: </strong>Combination therapy involving administration of DFO and CHC is effective in cancer cells wherein DFO treatment results in an elevation in lactate levels. Our findings illustrate that the DFO-induced enhanced glycolysis provides specific targets for developing an efficient anticancer combinatorial therapy involving DFO. These findings will be beneficial for the development of novel cancer chemotherapeutics.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"8"},"PeriodicalIF":5.9,"publicationDate":"2022-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10253333","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":"Identification of novel lipid biomarkers in xmrk- and Myc-induced models of hepatocellular carcinoma in zebrafish.","authors":"Jerry D Monroe,&nbsp;Daniel Fraher,&nbsp;Xiaoqian Huang,&nbsp;Natalie A Mellett,&nbsp;Peter J Meikle,&nbsp;Andrew J Sinclair,&nbsp;Seth T Lirette,&nbsp;Nita J Maihle,&nbsp;Zhiyuan Gong,&nbsp;Yann Gibert","doi":"10.1186/s40170-022-00283-y","DOIUrl":"https://doi.org/10.1186/s40170-022-00283-y","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and is accompanied by complex dysregulation of lipids. Increasing evidence suggests that particular lipid species are associated with HCC progression. Here, we aimed to identify lipid biomarkers of HCC associated with the induction of two oncogenes, xmrk, a zebrafish homolog of the human epidermal growth factor receptor (EGFR), and Myc, a regulator of EGFR expression during HCC.</p><p><strong>Methods: </strong>We induced HCC in transgenic xmrk, Myc, and xmrk/Myc zebrafish models. Liver specimens were histologically analyzed to characterize the HCC stage, Oil-Red-O stained to detect lipids, and liquid chromatography/mass spectrometry analyzed to assign and quantify lipid species. Quantitative real-time polymerase chain reaction was used to measure lipid metabolic gene expression in liver samples. Lipid species data was analyzed using univariate and multivariate logistic modeling to correlate lipid class levels with HCC progression.</p><p><strong>Results: </strong>We found that induction of xmrk, Myc and xmrk/Myc caused different stages of HCC. Lipid deposition and class levels generally increased during tumor progression, but triglyceride levels decreased. Myc appears to control early HCC stage lipid species levels in double transgenics, whereas xmrk may take over this role in later stages. Lipid metabolic gene expression can be regulated by either xmrk, Myc, or both oncogenes. Our computational models showed that variations in total levels of several lipid classes are associated with HCC progression.</p><p><strong>Conclusions: </strong>These data indicate that xmrk and Myc can temporally regulate lipid species that may serve as effective biomarkers of HCC progression.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"7"},"PeriodicalIF":5.9,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8981695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10268774","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":"Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas.","authors":"Evelyn de Groot, Sruthy Varghese, Lin Tan, Barbara Knighton, Mary Sobieski, Nghi Nguyen, Yong Sung Park, Reid Powell, Philip L Lorenzi, Bin Zheng, Clifford Stephan, Y N Vashisht Gopal","doi":"10.1186/s40170-022-00281-0","DOIUrl":"10.1186/s40170-022-00281-0","url":null,"abstract":"<p><strong>Background: </strong>Primary and posttreatment resistance to BRAF^V600 mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy.</p><p><strong>Methods: </strong>We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment.</p><p><strong>Results: </strong>A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation.</p><p><strong>Conclusions: </strong>STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"6"},"PeriodicalIF":6.0,"publicationDate":"2022-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310509","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":"Bendamustine","authors":"M. Kalaycio","doi":"10.1007/s40278-021-02015-2","DOIUrl":"https://doi.org/10.1007/s40278-021-02015-2","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"152 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76783514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies.","authors":"Daniel F Liefwalker, Meital Ryan, Zhichao Wang, Khyatiben V Pathak, Seema Plaisier, Vidhi Shah, Bobby Babra, Gabrielle S Dewson, Ian K Lai, Adriane R Mosley, Patrick T Fueger, Stephanie C Casey, Lei Jiang, Patrick Pirrotte, Srividya Swaminathan, Rosalie C Sears","doi":"10.1186/s40170-021-00263-8","DOIUrl":"10.1186/s40170-021-00263-8","url":null,"abstract":"<p><strong>Background: </strong>Metabolic reprogramming is a central feature in many cancer subtypes and a hallmark of cancer. Many therapeutic strategies attempt to exploit this feature, often having unintended side effects on normal metabolic programs and limited efficacy due to integrative nature of metabolic substrate sourcing. Although the initiating oncogenic lesion may vary, tumor cells in lymphoid malignancies often share similar environments and potentially similar metabolic profiles. We examined cells from mouse models of MYC-, RAS-, and BCR-ABL-driven lymphoid malignancies and find a convergence on de novo lipogenesis. We explore the potential role of MYC in mediating lipogenesis by ¹³C glucose tracing and untargeted metabolic profiling. Inhibition of lipogenesis leads to cell death both in vitro and in vivo and does not induce cell death of normal splenocytes.</p><p><strong>Methods: </strong>We analyzed RNA-seq data sets for common metabolic convergence in lymphoma and leukemia. Using in vitro cell lines derived in from conditional MYC, RAS, and BCR-ABL transgenic murine models and oncogene-driven human cell lines, we determined gene regulation, metabolic profiles, and sensitivity to inhibition of lipogenesis in lymphoid malignancies. We utilize preclinical murine models and transgenic primary model of T-ALL to determine the effect of lipogenesis blockade across BCR-ABL-, RAS-, and c-MYC-driven lymphoid malignancies. Statistical significance was calculated using unpaired t-tests and one-way ANOVA.</p><p><strong>Results: </strong>This study illustrates that de novo lipid biogenesis is a shared feature of several lymphoma subtypes. Using cell lines derived from conditional MYC, RAS, and BCR-ABL transgenic murine models, we demonstrate shared responses to inhibition of lipogenesis by the acetyl-coA carboxylase inhibitor 5-(tetradecloxy)-2-furic acid (TOFA), and other lipogenesis inhibitors. We performed metabolic tracing studies to confirm the influence of c-MYC and TOFA on lipogenesis. We identify specific cell death responses to TOFA in vitro and in vivo and demonstrate delayed engraftment and progression in vivo in transplanted lymphoma cell lines. We also observe delayed progression of T-ALL in a primary transgenic mouse model upon TOFA administration. In a panel of human cell lines, we demonstrate sensitivity to TOFA treatment as a metabolic liability due to the general convergence on de novo lipogenesis in lymphoid malignancies driven by MYC, RAS, or BCR-ABL. Importantly, cell death was not significantly observed in non-malignant cells in vivo.</p><p><strong>Conclusions: </strong>These studies suggest that de novo lipogenesis may be a common survival strategy for many lymphoid malignancies and may be a clinically exploitable metabolic liability.</p><p><strong>Trial registration: </strong>This study does not include any clinical interventions on human subjects.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"9 1","pages":"31"},"PeriodicalIF":5.9,"publicationDate":"2021-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9774557","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":"礫浜性マメアカイソガニ（モクズガニ科）の能登半島と九州沿岸からの記録","authors":"中岡 由起子, 恵次 和田","doi":"10.18988/CANCER.30.0_49","DOIUrl":"https://doi.org/10.18988/CANCER.30.0_49","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"183 1","pages":"49-56"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74622973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"日本初記録の2種を含む琉球列島産のヒラベニオウギガニ属（十脚目：短尾下目：オウギガニ科）","authors":"唯史 前之園","doi":"10.18988/CANCER.30.0_73","DOIUrl":"https://doi.org/10.18988/CANCER.30.0_73","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"73-79"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84670153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"日本初記録種を含む琉球列島産のシンオウギガニ亜科（甲殻亜門：十脚目：短尾下目：オウギガニ科）","authors":"唯史 前之園","doi":"10.18988/CANCER.30.0_21","DOIUrl":"https://doi.org/10.18988/CANCER.30.0_21","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"1 1","pages":"21-33"},"PeriodicalIF":5.9,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89252841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}