{"doi":"10.1101/2022.06.01.494055","title":"Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and rewires the microenvironment toward an immune-suppressive state","abstract":"Abstract mTORC1 regulates cell metabolism to enable cell proliferation, and is hyperactive in multiple cancer types 1, 2 . Here, we performed integrative analysis of single cell transcriptomic profiling, paired T cell receptor (TCR) sequencing, and spatial transcriptomic profiling on Tuberous Sclerosis Complex (TSC) associated tumors with mTORC1 hyperactivity, and identified a stem-like tumor cell state (SLS) linked to T cell dysfunction via tumor-modulated immunosuppressive macrophages. Rapamycin and its derivatives (rapalogs) are the primary treatments for TSC tumors, and the stem-like tumor cells showed rapamycin resistance in vitro , reminiscent of the cytostatic effects of these drugs in patients. The pro-angiogenic factor midkine (MDK) was highly expressed by the SLS population, and associated with enrichment of endothelial cells in SLS-dominant samples. Inhibition of MDK showed synergistic benefit with rapamycin in reducing the growth of TSC cell lines in vitro and in vivo . In aggregate, this study suggests an autocrine rapamycin resistance mechanism and a paracrine tumor survival mechanism via immune suppression adopted by the stem-like state tumor cells with mTORC1 hyperactivity. We also provide a comprehensive resource to advance the understanding of TSC and potentially other mTORC1-hyperactive tumors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":308976,"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":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":298782,"name":"David J. Kwiatkowski","orcid":"0000-0002-5668-5219","position":1,"is_corresponding":false},{"id":247628,"name":"Elizabeth P. Henske","orcid":"0000-0001-7978-6699","position":2,"is_corresponding":false},{"id":92231,"name":"Yan Tang","orcid":"0000-0002-6223-8423","position":0,"is_corresponding":true}],"reference_count":128,"raw_metadata":null,"created_at":"2026-07-19T00:33:07.132912Z","pmid":null,"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":[]}