ATF3 characterizes aggressive drug-tolerant persister cells in HGSOC

High-grade serous ovarian cancer (HGSOC) represents the most common and lethal subtype of ovarian cancer. Despite initial response to platinum-based standard therapy, patients commonly suffer from relapse that likely originates from drug-tolerant persister (DTP) cells. We generated isogenic clones o...

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Bibliographic Details
Published in:	Cell death & disease Vol. 15; no. 4; p. 290
Main Authors:	Böpple, Kathrin, Oren, Yaara, Henry, Whitney S., Dong, Meng, Weller, Sandra, Thiel, Julia, Kleih, Markus, Gaißler, Andrea, Zipperer, Damaris, Kopp, Hans-Georg, Aylon, Yael, Oren, Moshe, Essmann, Frank, Liang, Chunguang, Aulitzky, Walter E.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 24-04-2024 Springer Nature B.V Nature Publishing Group
Subjects:	13/1 13/109 13/89 45/91 631/67/1517/1709 631/67/2329 631/67/70 64/60 Activating transcription factor 3 Activating Transcription Factor 3 - genetics Activating Transcription Factor 3 - metabolism Animals Antibodies Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Cell death Cell Line, Tumor Cell lineage Cisplatin Cisplatin - pharmacology Cisplatin - therapeutic use Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Endoplasmic reticulum Epithelial cells Epithelial-Mesenchymal Transition - drug effects Epithelial-Mesenchymal Transition - genetics Female Gene Expression Regulation, Neoplastic - drug effects Humans Immunology Life Sciences Mice Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Platinum Ribonucleic acid RNA Solid tumors Xenograft Model Antitumor Assays Xenografts
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Summary:	High-grade serous ovarian cancer (HGSOC) represents the most common and lethal subtype of ovarian cancer. Despite initial response to platinum-based standard therapy, patients commonly suffer from relapse that likely originates from drug-tolerant persister (DTP) cells. We generated isogenic clones of treatment-naïve and cisplatin-tolerant persister HGSOC cells. In addition, single-cell RNA sequencing of barcoded cells was performed in a xenograft model with HGSOC cell lines after platinum-based therapy. Published single-cell RNA-sequencing data from neo-adjuvant and non-treated HGSOC patients and patient data from TCGA were analyzed. DTP-derived cells exhibited morphological alterations and upregulation of epithelial-mesenchymal transition (EMT) markers. An aggressive subpopulation of DTP-derived cells showed high expression of the stress marker ATF3 . Knockdown of ATF3 enhanced the sensitivity of aggressive DTP-derived cells to cisplatin-induced cell death, implying a role for ATF3 stress response in promoting a drug tolerant persister cell state. Furthermore, single cell lineage tracing to detect transcriptional changes in a HGSOC cell line-derived xenograft relapse model showed that cells derived from relapsed solid tumors express increased levels of EMT and multiple endoplasmic reticulum (ER) stress markers, including ATF3 . Single cell RNA sequencing of epithelial cells from four HGSOC patients also identified a small cell population resembling DTP cells in all samples. Moreover, analysis of TCGA data from 259 HGSOC patients revealed a significant progression-free survival advantage for patients with low expression of the ATF3 -associated partial EMT genes. These findings suggest that increased ATF3 expression together with partial EMT promote the development of aggressive DTP, and thereby relapse in HGSOC patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-024-06674-x