{"doi":"10.1016/j.jbc.2025.108495","title":"Patient-derived organotypic tissue cultures as a platform to evaluate metabolic reprogramming in breast cancer patients","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 + /PR + /HER2 - tumors while one came from a patient with neoadjuvant therapy for locally metastatic ER low /PR - /HER2 - 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 2 H 7 -glucose/ 13 C 5 , 15 N 2 -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 low /PR - /HER2 - 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":"Journal of Biological Chemistry","year":2025,"id":543680,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9216,"is_data_producer":true,"deposit_databanks":{"Dryad":["10.5061/dryad.4qrfj6qnm"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1433667,"name":"Jing Yan","orcid":"0009-0003-6118-5862","position":1,"is_corresponding":false},{"id":1428049,"name":"Carlos Frederico Lima Gonçalves","orcid":"0000-0003-2159-7400","position":2,"is_corresponding":false},{"id":1094401,"name":"Jahid M. M. Islam","orcid":"0000-0001-8846-2362","position":3,"is_corresponding":false},{"id":232992,"name":"Penghui Lin","orcid":"0000-0002-7733-7782","position":4,"is_corresponding":false},{"id":1433668,"name":"Mohamed M. Y. Kaddah","orcid":"0000-0003-0575-2458","position":5,"is_corresponding":false},{"id":228145,"name":"Richard M. Higashi","orcid":"0000-0002-3256-0622","position":6,"is_corresponding":false},{"id":228146,"name":"Andrew N. Lane","orcid":"0000-0003-1121-5106","position":7,"is_corresponding":false},{"id":473907,"name":"Xiaoqin Wang","orcid":"0000-0003-3880-8374","position":8,"is_corresponding":false},{"id":581179,"name":"Caigang Zhu","orcid":"0000-0001-5841-962X","position":9,"is_corresponding":false},{"id":228147,"name":"Teresa W.‐M. Fan","orcid":"0000-0002-7292-8938","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:53:08.338070Z","pmid":"40209948","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}