RT Journal Article
SR Electronic
T1 Phenotypic dissection of epithelial lineages and therapeutic manipulation of differentiation programs in human Adenoid Cystic Carcinomas (ACCs)
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.19.476843
DO 10.1101/2022.01.19.476843
A1 Sara Viragova
A1 Luis Aparicio
A1 Junfei Zhao
A1 Luis E. Valencia Salazar
A1 Alexandra Schurer
A1 Anika Dhuri
A1 Debashis Sahoo
A1 Christopher A. Moskaluk
A1 Raul Rabadan
A1 Piero Dalerba
YR 2022
UL http://biorxiv.org/content/early/2022/01/21/2022.01.19.476843.abstract
AB Adenoid Cystic Carcinoma (ACC) is a rare and aggressive form of salivary gland cancer, characterized by the co-existence within tumor tissues of two distinct populations of malignant cells, phenotypically similar to the myoepithelial and ductal lineages of normal salivary glands. Using a novel computational approach for single-cell RNA-seq analysis, we identified two cell-surface markers (CD49f, KIT) that enable the differential purification of myoepithelial-like (CD49fhigh/KITneg) and ductal-like (CD49flow/KIT+) cells from ACC patient derived xenografts (PDX). Using prospective xeno-transplantation experiments, we demonstrate that myoepithelial-like cells act as progenitors of ductal-like cells. Using three-dimensional (3D) organoid cultures, we demonstrate that agonists of retinoic acid (RA) signaling promote differentiation of myoepithelial-like cells into ductal-like cells, while inhibitors of RA signaling selectively kill ductal-like cells. Finally, we demonstrate that BMS493, an inverse agonist of RA signaling, can be successfully leveraged for the in vivo treatment of human ACCs.Competing Interest StatementSara Viragova is a co-inventor on a patent application (US-17/391,853), describing the use of inverse agonists of retinoic acid receptors as anti-tumor agents for the treatment of ACCs. Raul Rabadan is a founder of Genotwin, a consultant for Arquimea Research and a member of the SAB of AimedBio, in activities unrelated to the current study. Piero Dalerba is a co-inventor on a patent application (US-17/391,853), describing the use of inverse agonists of retinoic acid receptors as anti-tumor agents for the treatment of ACCs. Piero Dalerba received royalties from Oncomed Pharmaceuticals, Quanticel Pharmaceuticals and Forty Seven Inc., as a results of his acknowledgment as a co-inventor on patents granted to the University of Michigan (US-07723112) and Stanford University (US-09329170, US-09850483, US-10344094) and related to: 1) the discovery of surface markers for the differential purification of cancer stem cell populations from human malignancies; 2) the use of single-cell genomics technologies for the identification of pharmacological targets expressed in cancer stem cell populations; 3) the combination of anti-CD47 and anti-EGFR monoclonal antibodies for the treatment of human colon cancer. P.D. owns stock in Eli Lilly and Company. Piero Dalerbas spouse is employed by AstraZeneca, and owns stock in the following pharmaceutical companies: AbbVie, Amgen, AstraZeneca, Eli Lilly and Company, Gilead, GlaxoSmithKline, Johnson & Johnson, Merck & Co, Novartis, Pfizer.