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The developmental relationship linking these 2 cell types, and their differential vulnerability to antitumor treatments, remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using single-cell RNA sequencing, we identified cell-surface markers (CD49f, KIT) that enabled the differential purification of myoepithelial-like (CD49fhigh\/KITneg) and ductal-like (CD49flow\/KIT+) cells from patient-derived xenografts (PDXs) of human ACCs. Using prospective xenotransplantation experiments, we compared the tumor-initiating capacity of the 2 cell types and tested whether one could differentiate into the other. Finally, we searched for signaling pathways with differential activation between the 2 cell types and tested their role as lineage-specific therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Myoepithelial-like cells displayed higher tumorigenicity than ductal-like cells and acted as their progenitors. Myoepithelial-like and ductal-like cells displayed differential expression of genes encoding for suppressors and activators of retinoic acid signaling, respectively. Agonists of retinoic acid receptor (RAR) or retinoid X receptor (RXR) signaling (all-trans retinoic acid, bexarotene) promoted myoepithelial-to-ductal differentiation, whereas suppression of RAR\/RXR signaling with a dominant-negative RAR construct abrogated it. Inverse agonists of RAR\/RXR signaling (BMS493, AGN193109) displayed selective toxicity against ductal-like cells and in vivo antitumor activity against PDX models of human ACC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In human ACCs, myoepithelial-like cells act as progenitors of ductal-like cells, and myoepithelial-to-ductal differentiation is promoted by RAR\/RXR signaling. Suppression of RAR\/RXR signaling is lethal to ductal-like cells and represents a new therapeutic approach against human ACCs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jnci\/djad062","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T11:20:55Z","timestamp":1681212055000},"page":"838-852","source":"Crossref","is-referenced-by-count":15,"title":["Inverse agonists of retinoic acid receptor\/retinoid X receptor signaling as lineage-specific antitumor agents against human adenoid cystic carcinoma"],"prefix":"10.1093","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0598-1445","authenticated-orcid":false,"given":"Sara","family":"Viragova","sequence":"first","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Medical Center , New York, NY, USA"},{"name":"Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA"},{"name":"Columbia Stem Cell 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