Inverse agonists of RAR/RXR signaling as lineage-specific anti-tumor agents against human Adenoid Cystic Carcinoma

Autor: Sara Viragova, Luis Aparicio, Pierangela Palmerini, Junfei Zhao, Luis E Valencia Salazar, Alexandra Schurer, Anika Dhuri, Debashis Sahoo, Christopher A Moskaluk, Raul Rabadan, Piero Dalerba
Rok vydání: 2023
Předmět:
Zdroj: JNCI: Journal of the National Cancer Institute.
ISSN: 1460-2105
0027-8874
Popis: Background Adenoid Cystic Carcinoma (ACC) is a lethal malignancy of exocrine glands, characterized by the co-existence within tumor tissues of two distinct populations of cancer cells, phenotypically similar to the myoepithelial and ductal lineages of normal salivary epithelia. The developmental relationship linking these two cell-types, and their differential vulnerability to anti-tumor treatments, remain unknown. Methods Using single-cell RNA-sequencing (scRNA-seq), 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 (PDX) of human ACCs. Using prospective xeno-transplantation experiments, we compared the tumor-initiating capacity of the two cell-types, and tested whether one could differentiate into the other. Finally, we searched for signaling pathways with differential activation between the two cell-types and tested their role as lineage-specific therapeutic targets. Results 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 (ATRA, 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 anti-tumor activity against PDX models of ACC. Conclusions 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.
Databáze: OpenAIRE
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