{"doi":"10.1101/2024.04.03.587917","title":"Onco-Circuit Addiction and Onco-Nutrient mTORC1 Signaling Vulnerability in a Model of Aggressive T Cell Malignancy","abstract":"SUMMARY How genetic lesions drive cell transformation and whether they can be circumvented without compromising function of non-transformed cells are enduring questions in oncology. Here we show that in mature T cells—in which physiologic clonal proliferation is a cardinal feature— constitutive MYC transcription and Tsc1 loss in mice modeled aggressive human malignancy by reinforcing each other’s oncogenic programs. This cooperation was supported by MYC-induced large neutral amino acid transporter chaperone SLC3A2 and dietary leucine, which in synergy with Tsc1 deletion overstimulated mTORC1 to promote mitochondrial fitness and MYC protein overexpression in a positive feedback circuit. A low leucine diet was therapeutic even in late-stage disease but did not hinder T cell immunity to infectious challenge, nor impede T cell transformation driven by constitutive nutrient mTORC1 signaling via Depdc5 loss. Thus, mTORC1 signaling hypersensitivity to leucine as an onco-nutrient enables an onco-circuit, decoupling pathologic from physiologic utilization of nutrient acquisition pathways.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":496248,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9475,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":817989,"name":"Andrew Cornish","orcid":"0000-0001-6703-8503","position":1,"is_corresponding":false},{"id":240580,"name":"H. Mytrang","orcid":"0000-0002-3043-3902","position":2,"is_corresponding":false},{"id":654989,"name":"Julia S. Brunner","orcid":"0000-0002-3195-147X","position":3,"is_corresponding":false},{"id":872844,"name":"Ting-Wei Hsu","orcid":"0000-0003-0523-1118","position":4,"is_corresponding":false},{"id":1342813,"name":"Zijian Xu","orcid":"0000-0002-0006-5301","position":5,"is_corresponding":false},{"id":1018956,"name":"Isha Malik","orcid":null,"position":6,"is_corresponding":false},{"id":1028959,"name":"Chaucie Edwards","orcid":null,"position":7,"is_corresponding":false},{"id":240587,"name":"Kristelle J. Capistrano","orcid":"0000-0003-4349-9924","position":8,"is_corresponding":false},{"id":240584,"name":"Xian Zhang","orcid":"0000-0001-9674-7886","position":9,"is_corresponding":false},{"id":288441,"name":"Mark H. Ginsberg","orcid":"0000-0002-5685-5417","position":10,"is_corresponding":false},{"id":259813,"name":"Lydia W.S. Finley","orcid":"0000-0003-4023-7574","position":11,"is_corresponding":false},{"id":281051,"name":"Megan S. Lim","orcid":"0000-0002-0415-2867","position":12,"is_corresponding":false},{"id":246207,"name":"Steven M. Horwitz","orcid":"0000-0002-6399-2006","position":13,"is_corresponding":false},{"id":240589,"name":"Ming O. Li","orcid":"0000-0002-1383-0535","position":14,"is_corresponding":false},{"id":845683,"name":"Xinxin Wang","orcid":"0000-0001-8238-7832","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T02:09:23.333150Z","pmid":"38617314","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":[]}