{"doi":"10.1016/j.celrep.2021.108768","title":"CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition","abstract":"Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by a transcriptional coactivator fusion composed of cyclic AMP-regulated transcriptional coactivator 1 (CRTC1) and mastermind-like 2 (MAML2). The mechanisms by which the chimeric CRTC1/MAML2 (C1/M2) oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that C1/M2 induces transcriptional activation of the non-canonical peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant PGC-1α4, which regulates peroxisome proliferator-activated receptor gamma (PPARγ)-mediated insulin-like growth factor 1 (IGF-1) expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. C1/M2-positive tumors exhibit IGF-1 pathway activation, and small-molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1 receptor (IGF-1R) inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγ inhibition with inverse agonists. These results yield insights into the aberrant coregulatory functions of C1/M2 and identify a specific vulnerability that can be exploited for precision therapy.","journal":"Cell Reports","year":2021,"id":178173,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":574883,"name":"Kshitij Parag‐Sharma","orcid":"0000-0003-3638-0941","position":1,"is_corresponding":false},{"id":574884,"name":"Weida Gong","orcid":"0000-0002-0046-9277","position":2,"is_corresponding":false},{"id":575379,"name":"Monideepa Sengupta","orcid":null,"position":3,"is_corresponding":false},{"id":574885,"name":"Arindam Chatterjee","orcid":"0000-0002-2990-6389","position":4,"is_corresponding":false},{"id":574886,"name":"Erin C. Henry","orcid":"0000-0001-5653-1650","position":5,"is_corresponding":false},{"id":525126,"name":"Yi‐Hsuan Tsai","orcid":"0000-0003-2107-4300","position":6,"is_corresponding":false},{"id":72629,"name":"Michele C. Hayward","orcid":"0000-0003-0921-1368","position":7,"is_corresponding":false},{"id":367424,"name":"Siddharth Sheth","orcid":"0000-0002-1923-2309","position":8,"is_corresponding":false},{"id":499829,"name":"Renée Betancourt","orcid":"0000-0003-4466-0636","position":9,"is_corresponding":false},{"id":574887,"name":"Trevor Hackman","orcid":"0000-0001-9330-2398","position":10,"is_corresponding":false},{"id":575380,"name":"Ricardo J. Padilla","orcid":null,"position":11,"is_corresponding":false},{"id":13902,"name":"Joel S. Parker","orcid":"0000-0003-2080-6901","position":12,"is_corresponding":false},{"id":356329,"name":"Jimena Giudice","orcid":"0000-0002-3330-7784","position":13,"is_corresponding":false},{"id":574888,"name":"Colin A. Flaveny","orcid":"0000-0002-5391-715X","position":14,"is_corresponding":false},{"id":1882,"name":"D. Neil Hayes","orcid":"0000-0001-6203-7771","position":15,"is_corresponding":false},{"id":596148,"name":"Antonio L. Amelio","orcid":"0000-0002-6295-2694","position":16,"is_corresponding":false},{"id":574882,"name":"Adele M. Musicant","orcid":"0000-0001-8526-0677","position":0,"is_corresponding":true}],"reference_count":106,"raw_metadata":null,"created_at":"2026-07-18T23:47:36.112170Z","pmid":"33626346","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":[]}