{"doi":"10.1172/jci139807","title":"Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins","abstract":"Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that, although WT and heterozygous NF1-mutant hiPSCs-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contained the cells of origin for neurofibromas, both Nf1 alleles were inactivated in mouse Sox10+ cells, leading to classic nodular cutaneous and plexiform neurofibroma formation that completely recapitulated their human counterparts. Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that, in addition to regulating MAPK-mediated cell growth, NF1 loss also altered Schwann cell differentiation to promote neurofibroma development. Taken together, we established a complementary humanized neurofibroma explant and, to our knowledge, first-in-kind genetically engineered nodular cutaneous neurofibroma mouse models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation.","journal":"Journal of Clinical Investigation","year":2020,"id":58392,"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":73,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":305781,"name":"Corina Anastasaki","orcid":"0000-0002-9928-6488","position":1,"is_corresponding":false},{"id":305782,"name":"Zhiguo Chen","orcid":"0000-0001-6451-2265","position":2,"is_corresponding":false},{"id":305783,"name":"Tracey Shipman","orcid":"0009-0004-4497-7080","position":3,"is_corresponding":false},{"id":305784,"name":"Jason B. Papke","orcid":"0000-0001-5030-1184","position":4,"is_corresponding":false},{"id":306702,"name":"Kevin Yin","orcid":null,"position":5,"is_corresponding":false},{"id":295596,"name":"David H. Gutmann","orcid":"0000-0002-3127-5045","position":6,"is_corresponding":false},{"id":305785,"name":"Lu Q. Le","orcid":"0000-0003-2817-5382","position":7,"is_corresponding":false},{"id":305780,"name":"Juan Mo","orcid":"0000-0002-7655-7521","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T21:07:11.345501Z","pmid":"33108355","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":[]}