Inverse agonists of retinoic acid receptor/retinoid X receptor signaling as lineage-specific antitumor agents against human adenoid cystic carcinoma
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissionsoup.com..
BACKGROUND: Adenoid 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.
METHODS: 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.
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 (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.
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:115 |
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| Enthalten in: |
Journal of the National Cancer Institute - 115(2023), 7 vom: 06. Juli, Seite 838-852 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Viragova, Sara [VerfasserIn] |
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| Links: |
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| Themen: |
5688UTC01R |
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| Anmerkungen: |
Date Completed 17.07.2023 Date Revised 12.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/jnci/djad062 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM355445808 |
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| 100 | 1 | |a Viragova, Sara |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inverse agonists of retinoic acid receptor/retinoid X receptor signaling as lineage-specific antitumor agents against human adenoid cystic carcinoma |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 17.07.2023 | ||
| 500 | |a Date Revised 12.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissionsoup.com. | ||
| 520 | |a BACKGROUND: Adenoid 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 | ||
| 520 | |a METHODS: 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 | ||
| 520 | |a 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 (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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Receptors, Retinoic Acid |2 NLM | |
| 650 | 7 | |a Retinoid X Receptors |2 NLM | |
| 650 | 7 | |a Tretinoin |2 NLM | |
| 650 | 7 | |a 5688UTC01R |2 NLM | |
| 700 | 1 | |a Aparicio, Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Palmerini, Pierangela |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Junfei |e verfasserin |4 aut | |
| 700 | 1 | |a Valencia Salazar, Luis E |e verfasserin |4 aut | |
| 700 | 1 | |a Schurer, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Dhuri, Anika |e verfasserin |4 aut | |
| 700 | 1 | |a Sahoo, Debashis |e verfasserin |4 aut | |
| 700 | 1 | |a Moskaluk, Christopher A |e verfasserin |4 aut | |
| 700 | 1 | |a Rabadan, Raul |e verfasserin |4 aut | |
| 700 | 1 | |a Dalerba, Piero |e verfasserin |4 aut | |
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