ArticleJournal of the National Cancer Institute2023
Inverse agonists of retinoic acid receptor/retinoid X receptor signaling as lineage-specific antitumor agents against human adenoid cystic carcinoma.
Article in Journal of the National Cancer Institute, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Single-Nucleus Transcriptomes of Lacrimal Gland Adenoid Cystic Carcinoma With Different Growth Patterns.Head & neck · 2026Article
- Stress-relaxing granular bioprinting materials enable complex and uniform organoid self-organization.Nature materials · 2026Article
- Transcription Factors in the Pathogenesis of Schizophrenia.Life (Basel, Switzerland) · 2026Review
- Stress relaxing granular bioprinting materials enable complex and uniform organoid self-organization.bioRxiv : the preprint server for biology · 2025Article
- Current Insights on Salivary Gland Adenoid Cystic Carcinoma: Related Genes and Molecular Pathways.Genes · 2025Review
- The E2F4 transcriptional repressor is a key mechanistic regulator of colon cancer resistance tobioRxiv : the preprint server for biology · 2025Article
- A Narrative Overview of Retinoid X Receptor Inhibitors in Chronic Disease Management.Current drug research reviews · 2025Review
- Adenoid cystic carcinoma: insights from molecular characterization and therapeutic advances.MedComm · 2024Review
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundAdenoid cystic carcinoma (ACC) is a lethal malignancy of exocrine glands, characterized by the coexistence within tumor tissues of 2 distinct populations of cancer cells, phenotypically similar to the myoepithelial and ductal lineages of normal salivary epithelia. The developmental relationship linking these 2 cell types, and their differential vulnerability to antitumor treatments, remains unknown.
methodsUsing 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.
resultsMyoepithelial-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.
conclusionsIn 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.
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