Inverse agonists of retinoic acid receptor/retinoid X receptor signaling as lineage-specific antitumor agents against human adenoid cystic carcinoma

Author:

Viragova Sara1234ORCID,Aparicio Luis56ORCID,Palmerini Pierangela123ORCID,Zhao Junfei56ORCID,Valencia Salazar Luis E123ORCID,Schurer Alexandra12ORCID,Dhuri Anika1,Sahoo Debashis789ORCID,Moskaluk Christopher A10ORCID,Rabadan Raul56ORCID,Dalerba Piero1231112ORCID

Affiliation:

1. Department of Pathology and Cell Biology, Columbia University Medical Center , New York, NY, USA

2. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA

3. Columbia Stem Cell Initiative, Columbia University Medical Center , New York, NY, USA

4. Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University , New York, NY, USA

5. Program for Mathematical Genomics, Department of Systems Biology, Columbia University , New York, NY, USA

6. Department of Biomedical Informatics, Columbia University , New York, NY, USA

7. Department of Pediatrics, University of California San Diego , San Diego, CA, USA

8. Department of Computer Science and Engineering, University of California San Diego , San Diego, CA, USA

9. Rebecca and John Moores Comprehensive Cancer Center, University of California San Diego , San Diego, CA, USA

10. Department of Pathology, University of Virginia School of Medicine , Charlottesville, VA, USA

11. Department of Medicine, Columbia University Medical Center , New York, NY, USA

12. Digestive and Liver Disease Research Center, Columbia University Medical Center , New York, NY, USA

Abstract

Abstract 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.

Funder

National Institutes of Health

Adenoid Cystic Carcinoma Research Foundation

Damon Runyon Cancer Research Foundation

National Organization of Rare Disorders

Prostate Cancer Foundation

Columbia University’s Herbert Irving Comprehensive Cancer Center

Flow Cytometry Shared Resource

Molecular Pathology Shared Resource

Genomics and High Throughput Screening Shared Resource

National Cancer Institute Cancer Center Support

Irving Institute for Clinical and Translational Research

National Center for Advancing Translational Sciences Cooperative

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

Reference74 articles.

1. Adenoid cystic carcinoma: clinical and molecular features;Moskaluk;Head Neck Pathol,2013

2. Epidemiology, prognostic factors, and treatment of malignant submandibular gland tumors: a population-based cohort analysis;Lee;JAMA Otolaryngol Head Neck Surg,2015

3. Clinicopathological study of distant metastases of salivary adenoid cystic carcinoma;Gao;Int J Oral Maxillofac Surg,2013

4. Salivary gland carcinoma in Denmark 1990-2005: outcome and prognostic factors. Results of the Danish Head and Neck Cancer Group (DAHANCA);Bjorndal;Oral Oncol,2012

5. Determinants and patterns of survival in adenoid cystic carcinoma of the head and neck, including an analysis of adjuvant radiation therapy;Lloyd;Am J Clin Oncol,2011

Cited by 6 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3