{"doi":"10.1101/2025.07.17.665404","title":"ETS1 Orchestrates a Hybrid EMT Program Driving in vivo Metastasis and Immune Evasion","abstract":"Abstract Transcriptional Intratumoral heterogeneity (ITH) is a hallmark of aggressive cancers, yet how transcriptional ITH programs drive tumor metastasis and immune evasion in upper aerodigestive squamous cell carcinoma (UASCC) remains unclear. Through single-cell RNA sequencing analysis of UASCC cells and patient tumors, we uncovered a hybrid epithelial mesenchymal transition (hEMT) ITH program linked to metastatic dissemination. The transcription factor ETS1 was identified as a master regulator of the hEMT program, directly activating pro-metastatic genes and promoting distant spread in vivo. Unexpectedly, ETS1 also orchestrated an immune-cold tumor microenvironment by transcriptionally activating both STAT1 and PD-L1 (CD274) genes, suppressing T lymphocyte infiltration, and elevating immune checkpoint molecules. Clinically, ETS1-high tumors strongly correlated with poor survival and resistance to immune checkpoint blockade across multiple cohorts. Leveraging drug screens, we discovered that ETS1-high cancers are vulnerable to HSP90 inhibitors (e.g., Alvespimycin), which suppress ETS1 by disrupting HIF1A-mediated transcriptional activation. Together, our work reveals ETS1 as a dual driver of tumor distal metastasis and immune evasion in UASCC, while nominating HSP90 inhibition as a tailored treatment strategy for ETS1-driven tumors. These findings provide a roadmap for targeting aggressive ITH subsets and overcoming immunotherapy resistance.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":570631,"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":0.951,"is_data_producer":false,"deposit_databanks":null,"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":1141268,"name":"Talia A. Wenger","orcid":"0000-0001-6616-2780","position":1,"is_corresponding":false},{"id":879831,"name":"Chehyun Nam","orcid":"0000-0001-8604-2313","position":2,"is_corresponding":false},{"id":314963,"name":"Qian Yang","orcid":"0000-0002-2405-2396","position":3,"is_corresponding":false},{"id":1476534,"name":"D Arnaudov","orcid":null,"position":4,"is_corresponding":false},{"id":879832,"name":"Megha Sheth","orcid":"0009-0009-6730-2621","position":5,"is_corresponding":false},{"id":1476535,"name":"Zhixuan Jing","orcid":null,"position":6,"is_corresponding":false},{"id":1411016,"name":"Yuhao Pan","orcid":"0009-0003-6676-1531","position":7,"is_corresponding":false},{"id":1476201,"name":"José Eduardo Vargas","orcid":"0000-0002-7729-5738","position":8,"is_corresponding":false},{"id":105721,"name":"Yong Teng","orcid":"0000-0002-1856-7289","position":9,"is_corresponding":false},{"id":729619,"name":"Uttam K. Sinha","orcid":"0000-0003-4208-8904","position":10,"is_corresponding":false},{"id":1087896,"name":"Young Min Park","orcid":"0000-0002-7593-8461","position":11,"is_corresponding":false},{"id":249497,"name":"De‐Chen Lin","orcid":"0000-0002-1951-367X","position":12,"is_corresponding":false},{"id":408939,"name":"Benjamin Ziman","orcid":"0000-0003-0951-3534","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:57:11.713851Z","pmid":"40777467","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":[]}