{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Fan TW"],"funding":["NIBIB NIH HHS","NCI NIH HHS","National Institutes of Health","NIGMS NIH HHS"],"pagination":["108495"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12137166"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["301(5)"],"pubmed_abstract":["Patient-derived organotypic tissue cultures (PD-OTC) are unique models for probing cancer metabolism and therapeutic responses. They retain patient tissue architectures/microenvironments that are difficult to recapitulate while affording comparison of cancer (CA) versus matched noncancer (NC) tissue responses to treatments. We have developed a long-term culturing method for fresh and cryopreserved PD-OTC of breast cancer patients bearing invasive ductal carcinoma. Five PD-OTC came from patients with treatment-naïve primary ER<sup>+</sup>/PR<sup>+</sup>/HER2<sup>-</sup> tumors while one came from a patient with neoadjuvant therapy for locally metastatic ER<sup>low</sup>/PR<sup>-</sup>/HER2<sup>-</sup> tumor. They all exhibited tissue outgrowth in 1 month with some CA OTC harboring isolatable organoids and fibroblasts. We interrogated reprogrammed metabolism in CA versus paired NC OTC with dual <sup>2</sup>H<sub>7</sub>-glucose/<sup>13</sup>C<sub>5</sub>,<sup>15</sup>N<sub>2</sub>-Gln tracers coupled with stable isotope-resolved metabolomic analysis. We noted variable activation of glycolysis, cataplerotic/anaplerotic Krebs cycle including reductive carboxylation, the pentose phosphate pathway, riboneogenesis, gluconeogenesis, de novo and salvage synthesis of purine/pyrimidine nucleotides, and ADP-ribosylation in CA PD-OTC. Altered metabolic activities were in part accountable by expression changes in key enzymes measured by reverse phase protein array profiling. Notably, Gln-fueled gluconeogenesis products were preferentially diverted to support purine nucleotide synthesis. When blocking this novel process with an inhibitor of phosphoenolpyruvate carboxykinase (3-mercaptopicolinic acid), metastatic, ER<sup>low</sup>/PR<sup>-</sup>/HER2<sup>-</sup> CA OTC displayed compromised cellularity, reduced outgrowth, and disrupted growth/survival-supporting metabolism but the matched NC OTC did not. Thus, our PD-OTC culturing method not only promoted understanding of actual patient's tumor metabolism to uncover viable metabolic targets but also enabled target testing and elucidation of therapeutic efficacy."],"journal":["The Journal of biological chemistry"],"pubmed_title":["Patient-derived organotypic tissue cultures as a platform to evaluate metabolic reprogramming in breast cancer patients."],"pmcid":["PMC12137166"],"funding_grant_id":["P30 CA177558","P30CA177558","5P20GM121327","R21EB032515","P20 GM121327","R21 EB032515"],"pubmed_authors":["Kaddah MMY","Lin P","Yan J","Goncalves CFL","Higashi RM","Islam JMM","Wang X","Fan TW","Lane AN","Zhu C"],"additional_accession":[]},"is_claimable":false,"name":"Patient-derived organotypic tissue cultures as a platform to evaluate metabolic reprogramming in breast cancer patients.","description":"Patient-derived organotypic tissue cultures (PD-OTC) are unique models for probing cancer metabolism and therapeutic responses. They retain patient tissue architectures/microenvironments that are difficult to recapitulate while affording comparison of cancer (CA) versus matched noncancer (NC) tissue responses to treatments. We have developed a long-term culturing method for fresh and cryopreserved PD-OTC of breast cancer patients bearing invasive ductal carcinoma. Five PD-OTC came from patients with treatment-naïve primary ER<sup>+</sup>/PR<sup>+</sup>/HER2<sup>-</sup> tumors while one came from a patient with neoadjuvant therapy for locally metastatic ER<sup>low</sup>/PR<sup>-</sup>/HER2<sup>-</sup> tumor. They all exhibited tissue outgrowth in 1 month with some CA OTC harboring isolatable organoids and fibroblasts. We interrogated reprogrammed metabolism in CA versus paired NC OTC with dual <sup>2</sup>H<sub>7</sub>-glucose/<sup>13</sup>C<sub>5</sub>,<sup>15</sup>N<sub>2</sub>-Gln tracers coupled with stable isotope-resolved metabolomic analysis. We noted variable activation of glycolysis, cataplerotic/anaplerotic Krebs cycle including reductive carboxylation, the pentose phosphate pathway, riboneogenesis, gluconeogenesis, de novo and salvage synthesis of purine/pyrimidine nucleotides, and ADP-ribosylation in CA PD-OTC. Altered metabolic activities were in part accountable by expression changes in key enzymes measured by reverse phase protein array profiling. Notably, Gln-fueled gluconeogenesis products were preferentially diverted to support purine nucleotide synthesis. When blocking this novel process with an inhibitor of phosphoenolpyruvate carboxykinase (3-mercaptopicolinic acid), metastatic, ER<sup>low</sup>/PR<sup>-</sup>/HER2<sup>-</sup> CA OTC displayed compromised cellularity, reduced outgrowth, and disrupted growth/survival-supporting metabolism but the matched NC OTC did not. Thus, our PD-OTC culturing method not only promoted understanding of actual patient's tumor metabolism to uncover viable metabolic targets but also enabled target testing and elucidation of therapeutic efficacy.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 May","modification":"2026-05-29T14:39:22.287Z","creation":"2025-07-26T03:06:36.715Z"},"accession":"S-EPMC12137166","cross_references":{"pubmed":["40209948"],"doi":["10.1016/j.jbc.2025.108495"]}}