Scholars@Duke publication: Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma.

Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma.

Publication , Journal Article

Jewell, ML; Gibson, JR; Guy, CD; Hyun, J; Du, K; Oh, S-H; Premont, RT; Hsu, DS; Ribar, T; Gregory, SG; Diehl, AME

Published in: Am J Pathol

January 2020

Fibrolamellar carcinoma (FLC) is characterized by in-frame fusion of DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1) with protein kinase cAMP-activated catalytic subunit α (PRKACA) and by dense desmoplasia. Surgery is the only effective treatment because mechanisms supporting tumor survival are unknown. We used single-cell RNA sequencing to characterize a patient-derived FLC xenograft model and identify therapeutic targets. Human FLC cells segregated into four discrete clusters that all expressed the oncogene Yes-associated protein 1 (YAP1). The two communities most enriched with cells coexpressing FLC markers [CD68, A-kinase anchoring protein 12 (AKAP12), cytokeratin 7, epithelial cell adhesion molecule (EPCAM), and carbamoyl palmitate synthase-1] also had the most cells expressing YAP1 and its proproliferative target genes (AREG and CCND1), suggesting these were proliferative FLC cell clusters. The other two clusters were enriched with cells expressing profibrotic YAP1 target genes, ACTA2, ELN, and COL1A1, indicating these were fibrogenic FLC cells. All clusters expressed the YAP1 target gene and mesothelial progenitor marker mesothelin, and many mesothelin-positive cells coexpressed albumin. Trajectory analysis predicted that the four FLC communities were derived from a single cell type transitioning among phenotypic states. After establishing a novel FLC cell line that harbored the DNAJB1-PRKACA fusion, YAP1 was inhibited, which significantly reduced expression of known YAP1 target genes as well as cell growth and migration. Thus, both FLC epithelial and stromal cells appear to arise from DNAJB1-PRKACA fusion in a YAP1-dependent liver mesothelial progenitor, identifying YAP1 as a target for FLC therapy.

Duke Scholars

Author Cynthia Dianne Guy Pathology

Author Kuo Du Medicine, Gastroenterology

Author Simon Gray Gregory Neurosurgery

Author Anna Mae Diehl Medicine, Gastroenterology

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Published In

Am J Pathol

DOI

10.1016/j.ajpath.2019.09.018

EISSN

1525-2191

Publication Date

January 2020

Volume

190

Issue

Start / End Page

93 / 107

Location

United States

Related Subject Headings

YAP-Signaling Proteins
Xenograft Model Antitumor Assays
Tumor Cells, Cultured
Transcription Factors
Stem Cells
Single-Cell Analysis
Pathology
Mice, SCID
Mice
Mesothelin

Citation

APA

Chicago

ICMJE

MLA

NLM

Jewell, M. L., Gibson, J. R., Guy, C. D., Hyun, J., Du, K., Oh, S.-H., … Diehl, A. M. E. (2020). Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma. Am J Pathol, 190(1), 93–107. https://doi.org/10.1016/j.ajpath.2019.09.018

Jewell, Mark L., Jason R. Gibson, Cynthia D. Guy, Jeongeun Hyun, Kuo Du, Seh-Hoon Oh, Richard T. Premont, et al. “Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma.” Am J Pathol 190, no. 1 (January 2020): 93–107. https://doi.org/10.1016/j.ajpath.2019.09.018.

Jewell ML, Gibson JR, Guy CD, Hyun J, Du K, Oh S-H, et al. Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma. Am J Pathol. 2020 Jan;190(1):93–107.

Jewell, Mark L., et al. “Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma.” Am J Pathol, vol. 190, no. 1, Jan. 2020, pp. 93–107. Pubmed, doi:10.1016/j.ajpath.2019.09.018.

Jewell ML, Gibson JR, Guy CD, Hyun J, Du K, Oh S-H, Premont RT, Hsu DS, Ribar T, Gregory SG, Diehl AME. Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma. Am J Pathol. 2020 Jan;190(1):93–107.