Cancer & Metabolism最新文献

{"title":"Metabolic profiling reveals metabolic features of consolidation therapy in pediatric acute lymphoblastic leukemia.","authors":"Jinqiu Fu,&nbsp;Aijun Zhang,&nbsp;Qinqin Liu,&nbsp;Dong Li,&nbsp;Xiaoming Wang,&nbsp;Libo Si","doi":"10.1186/s40170-023-00302-6","DOIUrl":"https://doi.org/10.1186/s40170-023-00302-6","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) and its treatment continue to pose substantial risks. To understand ALL more deeply, the metabolome in fasting plasma of 27 ALL patients before and after high-dose methotrexate therapies (consolidation therapy) including methotrexate and 6-mercaptopurine (6-MP) was investigated. Plasma metabolites were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS). Orthogonal projections to latent structures discriminant analysis and significance analysis of microarrays were used to evaluate the metabolic changes. Pathway enrichment and co-expression network analyses were performed to identify clusters of molecules, and 2826 metabolites were identified. Among them, 38 metabolites were identified by univariate analysis, and 7 metabolites that were altered by conditioning therapy were identified by multivariate analysis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used for pathway enrichment analysis. Among the enriched KEGG pathways, the 3 significantly altered metabolic pathways were pyrimidine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; and phenylalanine metabolism. In addition, L-phenylalanine was significantly correlated with blood urea nitrogen (BUN), and palmitoylcarnitine was correlated with aspartate aminotransferase (AST). In summary, consolidation therapy significantly affected pyrimidine- and phenylalanine-associated metabolic pathways in pediatric ALL patients. These findings may provide an insight into the role of metabolic profiling in consolidation treatment and as a potential for pediatric ALL patients.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"2"},"PeriodicalIF":5.9,"publicationDate":"2023-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9869545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10667406","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":"Arginase-1 inhibition reduces migration ability and metastatic colonization of colon cancer cells.","authors":"Xiangdong Wang,&nbsp;Huihui Xiang,&nbsp;Yujiro Toyoshima,&nbsp;Weidong Shen,&nbsp;Shunsuke Shichi,&nbsp;Hiroki Nakamoto,&nbsp;Saori Kimura,&nbsp;Ko Sugiyama,&nbsp;Shigenori Homma,&nbsp;Yohei Miyagi,&nbsp;Akinobu Taketomi,&nbsp;Hidemitsu Kitamura","doi":"10.1186/s40170-022-00301-z","DOIUrl":"https://doi.org/10.1186/s40170-022-00301-z","url":null,"abstract":"<p><strong>Background: </strong>Arginase-1 (ARG1), a urea cycle-related enzyme, catalyzes the hydrolysis of arginine to urea and ornithine, which regulates the proliferation, differentiation, and function of various cells. However, it is unclear whether ARG1 controls the progression and malignant alterations of colon cancer.</p><p><strong>Methods: </strong>We established metastatic colonization mouse model and ARG1 overexpressing murine colon cancer CT26 cells to investigate whether activation of ARG1 was related to malignancy of colon cancer cells in vivo. Living cell numbers and migration ability of CT26 cells were evaluated in the presence of ARG inhibitor in vitro.</p><p><strong>Results: </strong>Inhibition of arginase activity significantly suppressed the proliferation and migration ability of CT26 murine colon cancer cells in vitro. Overexpression of ARG1 in CT26 cells reduced intracellular L-arginine levels, enhanced cell migration, and promoted epithelial-mesenchymal transition. Metastatic colonization of CT26 cells in lung and liver tissues was significantly augmented by ARG1 overexpression in vivo. ARG1 gene expression was higher in the tumor tissues of liver metastasis than those of primary tumor, and arginase inhibition suppressed the migration ability of HCT116 human colon cancer cells.</p><p><strong>Conclusion: </strong>Activation of ARG1 is related to the migration ability and metastatic colonization of colon cancer cells, and blockade of this process may be a novel strategy for controlling cancer malignancy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"1"},"PeriodicalIF":5.9,"publicationDate":"2023-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9838026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9080180","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":"Functional noninvasive detection of glycolytic pancreatic ductal adenocarcinoma.","authors":"Irina Heid,&nbsp;Corinna Münch,&nbsp;Sinan Karakaya,&nbsp;Smiths S Lueong,&nbsp;Alina M Winkelkotte,&nbsp;Sven T Liffers,&nbsp;Laura Godfrey,&nbsp;Phyllis F Y Cheung,&nbsp;Konstantinos Savvatakis,&nbsp;Geoffrey J Topping,&nbsp;Florian Englert,&nbsp;Lukas Kritzner,&nbsp;Martin Grashei,&nbsp;Andrea Tannapfel,&nbsp;Richard Viebahn,&nbsp;Heiner Wolters,&nbsp;Waldemar Uhl,&nbsp;Deepak Vangala,&nbsp;Esther M M Smeets,&nbsp;Erik H J G Aarntzen,&nbsp;Daniel Rauh,&nbsp;Wilko Weichert,&nbsp;Jörg D Hoheisel,&nbsp;Stephan A Hahn,&nbsp;Franz Schilling,&nbsp;Rickmer Braren,&nbsp;Marija Trajkovic-Arsic,&nbsp;Jens T Siveke","doi":"10.1186/s40170-022-00298-5","DOIUrl":"https://doi.org/10.1186/s40170-022-00298-5","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) lacks effective treatment options beyond chemotherapy. Although molecular subtypes such as classical and QM (quasi-mesenchymal)/basal-like with transcriptome-based distinct signatures have been identified, deduced therapeutic strategies and targets remain elusive. Gene expression data show enrichment of glycolytic genes in the more aggressive and therapy-resistant QM subtype. However, whether the glycolytic transcripts are translated into functional glycolysis that could further be explored for metabolic targeting in QM subtype is still not known.</p><p><strong>Methods: </strong>We used different patient-derived PDAC model systems (conventional and primary patient-derived cells, patient-derived xenografts (PDX), and patient samples) and performed transcriptional and functional metabolic analysis. These included RNAseq and Illumina HT12 bead array, in vitro Seahorse metabolic flux assays and metabolic drug targeting, and in vivo hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate magnetic resonance spectroscopy (HP-MRS) in PDAC xenografts.</p><p><strong>Results: </strong>We found that glycolytic metabolic dependencies are not unambiguously functionally exposed in all QM PDACs. Metabolic analysis demonstrated functional metabolic heterogeneity in patient-derived primary cells and less so in conventional cell lines independent of molecular subtype. Importantly, we observed that the glycolytic product lactate is actively imported into the PDAC cells and used in mitochondrial oxidation in both classical and QM PDAC cells, although more actively in the QM cell lines. By using HP-MRS, we were able to noninvasively identify highly glycolytic PDAC xenografts by detecting the last glycolytic enzymatic step and prominent intra-tumoral [1-¹³C]pyruvate and [1-¹³C]lactate interconversion in vivo.</p><p><strong>Conclusion: </strong>Our study adds functional metabolic phenotyping to transcriptome-based analysis and proposes a functional approach to identify highly glycolytic PDACs as candidates for antimetabolic therapeutic avenues.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"24"},"PeriodicalIF":5.9,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10329732","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":"PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFβ1-promoted stem-like properties in head and neck cancer.","authors":"Wan-Hsuan Sun,&nbsp;Yun-Hsuan Chen,&nbsp;Hou-Hsuan Lee,&nbsp;Yu-Wen Tang,&nbsp;Kuang-Hui Sun","doi":"10.1186/s40170-022-00300-0","DOIUrl":"https://doi.org/10.1186/s40170-022-00300-0","url":null,"abstract":"<p><strong>Background: </strong>Resistance to chemotherapeutic drugs is a key factor for cancer recurrence and metastases in head and neck cancer (HNC). Cancer stem cells (CSCs) in tumors have self-renewal, differentiation, and higher drug resistance capabilities, resulting in a poor prognosis for patients. In glucose metabolism, pyruvate dehydrogenase kinase (PDK) inhibits pyruvate dehydrogenase and impedes pyruvate from being metabolized into acetyl-CoA and entering the tricarboxylic acid cycle to generate energy. Studies have reported that PDK1 and PDK2 inhibition suppresses the growth, motility, and drug resistance of cancer cells. Furthermore, while TGFβ1 levels are persistently elevated in HNC patients with poor prognosis, the role of PDK isoforms in the TGFβ1-promoted progression and stem-like properties of HNC is unclear.</p><p><strong>Methods: </strong>Levels of PDK1 and PDK2 were evaluated in HNC tissue microarrays by immunohistochemistry to explore potential clinical relevance. PDK1 and PDK2 were knocked down by the lentivirus shRNA system to investigate their role in TGFβ1-promoted tumor progression in vitro.</p><p><strong>Results: </strong>We found that PDK2 levels were increased in the later stage of HNC tissues compared to constant PDK1 expression. After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFβ1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFβ1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance.</p><p><strong>Conclusion: </strong>The results demonstrated that the PDK1- and PDK2-mediated Warburg effect contributes to the TGFβ1-enhanced stemness properties of HNC. Therefore, PDK1 and PDK2 may serve as molecular targets for the combination therapy of HNC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"23"},"PeriodicalIF":5.9,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10430523","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":"Tadalafil increases the antitumor activity of 5-FU through inhibiting PRMT5-mediated glycolysis and cell proliferation in colorectal cancer.","authors":"Yao Shen,&nbsp;Pan Zhao,&nbsp;Kewei Dong,&nbsp;Jiajia Wang,&nbsp;Huichen Li,&nbsp;Mengyang Li,&nbsp;Ruikai Li,&nbsp;Suning Chen,&nbsp;Yuxia Shen,&nbsp;Zhiyu Liu,&nbsp;Mianjiao Xie,&nbsp;Peng Shen,&nbsp;Jian Zhang","doi":"10.1186/s40170-022-00299-4","DOIUrl":"https://doi.org/10.1186/s40170-022-00299-4","url":null,"abstract":"<p><strong>Background: </strong>Protein arginine methyltransferase 5 (PRMT5) is upregulated in multiple tumors and plays a pivotal role in cancer cell proliferation. However, the role of PRMT5 in colorectal cancer remains poorly understood.</p><p><strong>Methods: </strong>We detected the expression level of PRMT5 and glycolytic enzymes using online databases and colorectal cancer cell lines by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. And MTT and colony formation assays were conducted to investigate cell proliferation. Then, we evaluated ECAR and OCR levels using a biological energy analyzer to investigate the energy status of colorectal cancer, and the transcriptional regulation was detected by dual luciferase reporter assay and ChIP assay. Finally, the efficacy of combined treatment of tadalafil and 5-FU was verified.</p><p><strong>Results: </strong>PRMT5 was highly expressed in colorectal cancer tissues compared with their normal counterparts and correlated with poor prognosis in CRC patients. Then, we demonstrated that PRMT5 knockdown or loss of function attenuated the viability of CRC cells, while overexpression of PRMT5 promoted cell proliferation. Mechanistically, PRMT5 enhanced glycolysis through transcriptionally activating LDHA expression. In addition, the PRMT5 inhibitor, tadalafil, rendered CRC cells sensitive to antitumor agent 5-FU in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our data indicates that PRMT5 promoted colorectal cancer proliferation partially through activating glycolysis and may be a potential target for colorectal cancer therapy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"22"},"PeriodicalIF":5.9,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10719378","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":"Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity.","authors":"Xinyi Zhang,&nbsp;Alexandra A Halberstam,&nbsp;Wanling Zhu,&nbsp;Brooks P Leitner,&nbsp;Durga Thakral,&nbsp;Marcus W Bosenberg,&nbsp;Rachel J Perry","doi":"10.1186/s40170-022-00296-7","DOIUrl":"https://doi.org/10.1186/s40170-022-00296-7","url":null,"abstract":"<p><strong>Background: </strong>Research about tumor \"metabolic flexibility\"-the ability of cells to toggle between preferred nutrients depending on the metabolic context-has largely focused on obesity-associated cancers. However, increasing evidence for a key role for nutrient competition in the tumor microenvironment, as well as for substrate regulation of immune function, suggests that substrate metabolism deserves reconsideration in immunogenic tumors that are not strongly associated with obesity.</p><p><strong>Methods: </strong>We compare two murine models: immunologically cold YUMM1.7 and immunologically-hot YUMMER1.7. We utilize stable isotope and radioisotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics analyses to comprehensively probe substrate preference in YUMM1.7 and YUMMER1.7 cells, with a subset of studies on the impact of available metabolites across a panel of five additional melanoma cell lines. We analyze bulk RNA-seq data and identify increased expression of amino acid and glucose metabolism genes in YUMMER1.7. Finally, we analyze melanoma patient RNA-seq data to identify potential prognostic predictors rooted in metabolism.</p><p><strong>Results: </strong>We demonstrate using stable isotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics that immunologically-hot melanoma utilizes more glutamine than immunologically-cold melanoma in vivo and in vitro. Analyses of human melanoma RNA-seq data demonstrate that glutamine transporter and other anaplerotic gene expression positively correlates with lymphocyte infiltration and function.</p><p><strong>Conclusions: </strong>Here, we highlight the importance of understanding metabolism in non-obesity-associated cancers, such as melanoma. This work advances the understanding of the correlation between metabolism and immunogenicity in the tumor microenvironment and provides evidence supporting metabolic gene expression as potential prognostic factors of melanoma progression and may inform investigations of adjunctive metabolic therapy in melanoma.</p><p><strong>Trial registration: </strong>Deidentified data from The Cancer Genome Atlas were analyzed.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"21"},"PeriodicalIF":5.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10061099","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":"Blocking lncRNA-SNHG16 sensitizes gastric cancer cells to 5-Fu through targeting the miR-506-3p-PTBP1-mediated glucose metabolism.","authors":"Yan Ding,&nbsp;Sujie Gao,&nbsp;Jiabin Zheng,&nbsp;Xuebo Chen","doi":"10.1186/s40170-022-00293-w","DOIUrl":"https://doi.org/10.1186/s40170-022-00293-w","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is a commonly occurring human malignancy. The 5-fluorouracil (5-Fu) is a first-line anti-gastric cancer agent. However, a large number of GC patients developed 5-Fu resistance. Currently, the roles and molecular mechanisms of the lncRNA-SNHG16-modulated 5-Fu resistance in gastric cancer remain elusive.</p><p><strong>Methods: </strong>Expressions of lncRNA, miRNA, and mRNA were detected by qRT-PCR and Western blot. RNA-RNA interaction was examined by RNA pull-down and luciferase assay. Cell viability and apoptosis rate under 5-Fu treatments were determined by MTT assay and Annexin V assay. The glycolysis rate of GC cells was evaluated by glucose uptake and ECAR.</p><p><strong>Results: </strong>Here, we report that SNHG16 as well as PTBP1, which is an RNA-binding protein, are positively associated with 5-Fu resistance to gastric cancer. SNHG16 and PTBP1 were significantly upregulated in gastric tumors and cell lines. Silencing SNHG16 or PTBP1 effectively sensitized GC cells to 5-Fu. Furthermore, glucose metabolism was remarkedly elevated in 5-Fu-resistant GC cells. Under low glucose supply, 5-Fu-resistant cells displayed higher vulnerability than parental GC cells. Bioinformatic analysis and luciferase assay demonstrated that SNHG16 downregulated miR-506-3p by sponging it to form a ceRNA network. We identified PTBP1 as a direct target of miR-506-3p in GC cells. RNA-seq results unveiled that PTBP1 positively regulated expressions of multiple glycolysis enzymes, including GLUT1, HK2, and LDHA. Bioinformatic analysis illustrated the 3'UTRs of glycolysis enzymes contained multiple PTBP1 binding sites, which were further verified by RNA pull-down and RNA immunoprecipitation assays. Consequently, we demonstrated that PTBP1 upregulated the mRNAs of glycolysis enzymes via promoting their mRNA stabilities. Finally, in vivo xenograft experiments validated that blocking the SNHG16-mediated miR-506-3p-PTBP1 axis effectively limited 5-Fu-resistant GC cell originated-xenograft tumor growth under 5-Fu treatments.</p><p><strong>Conclusions: </strong>Our study demonstrates molecular mechanisms of the SNHG16-mediated 5-Fu resistance of GC cells through modulating the miR-506-3p-PTBP1-glucose metabolism axis, presenting a promising approach for anti-chemoresistance therapy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"20"},"PeriodicalIF":5.9,"publicationDate":"2022-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9707261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10694564","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":"Altered acetyl-CoA metabolism presents a new potential immunotherapy target in the obese lung microenvironment.","authors":"Spencer R Rosario,&nbsp;Randall J Smith,&nbsp;Santosh K Patnaik,&nbsp;Song Liu,&nbsp;Joseph Barbi,&nbsp;Sai Yendamuri","doi":"10.1186/s40170-022-00292-x","DOIUrl":"https://doi.org/10.1186/s40170-022-00292-x","url":null,"abstract":"<p><p>Contrary to the \"obesity paradox,\" which arises from retrospective studies relying on body mass index to define obesity, epidemiologic evidence suggests central or visceral obesity is associated with a higher risk for the development of lung cancer. About 60% of individuals at high risk for developing lung cancer or those already with early-stage disease are either overweight or obese. Findings from resected patient tumors and mouse lung tumor models show obesity dampens immune activity in the tumor microenvironment (TME) encouraging disease progression. In line with this, we have observed a marked, obesity-specific enhancement in the presence and phenotype of immunosuppressive regulatory T (Treg) cells in murine tumors as well as the airways of both humans and mice. Leveraging direct metabolomic measurements and robust inferred analyses from RNA-sequencing data, we here demonstrate for the first time that visceral adiposity alters the lung microenvironment via dysregulated acetyl-CoA metabolism in a direction that facilitates immune suppression and lung carcinogenesis.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"17"},"PeriodicalIF":5.9,"publicationDate":"2022-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9620073","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":"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}