{"doi":"10.7554/elife.93170","title":"Metastatic small cell lung cancer arises from TP53/RB1-deficient and MYC overproduction hESC-derived PNECs","abstract":"We previously described our initial efforts to develop a model for small cell lung cancer (SCLC) derived from human embryonic stem cells (hESCs) that were differentiated to form pulmonary neuroendocrine cells (PNECs), a putative cell of origin for neuroendocrine-positive SCLC. Although reduced expression of the tumor suppressor genes TP53 and RB1 allowed the induced PNECs to form subcutaneous growths in immune-deficient mice, the tumors did not display the aggressive characteristics of SCLC seen in human patients. Here, we report that the additional, doxycycline-regulated expression of a transgene encoding wild-type or mutant MYC protein promotes rapid growth, invasion, and metastasis of these hESC-derived cells after injection into the renal capsule. Similar to others, we find that the addition of MYC encourages the formation of the SCLC-N subtype, marked by high levels of NEUROD1 RNA. Using paired primary and metastatic samples for RNA-sequencing, we observe that the subtype of SCLC does not change upon metastatic spread and that production of NEUROD1 is maintained. We also describe histological features of these malignant, SCLC-like tumors derived from hESCs and discuss potential uses of this model in efforts to control and better understand this recalcitrant neoplasm.","journal":"eLife","year":2024,"id":485359,"datarank":0.2714785147021382,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.002714594317929922,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.002714594317929922,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":4,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE255757"]},"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":822241,"name":"Eric E. Gardner","orcid":"0000-0002-1552-2675","position":1,"is_corresponding":false},{"id":328463,"name":"Yajas Shah","orcid":"0000-0002-9692-4878","position":2,"is_corresponding":false},{"id":1170044,"name":"Kui Zhang","orcid":"0000-0001-9618-610X","position":3,"is_corresponding":false},{"id":1170045,"name":"Abhimanyu Thakur","orcid":"0000-0002-0846-0998","position":4,"is_corresponding":false},{"id":513464,"name":"Chen Zhang","orcid":"0000-0002-5080-9321","position":5,"is_corresponding":false},{"id":41043,"name":"Olivier Elemento","orcid":"0000-0002-8061-9617","position":6,"is_corresponding":false},{"id":1271,"name":"Harold Varmus","orcid":"0000-0002-6444-1943","position":7,"is_corresponding":false},{"id":109230,"name":"Huanhuan Joyce Chen","orcid":"0000-0002-1446-7184","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:07:47.633574Z","pmid":"40694497","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":[]}