ATF3 characterizes aggressive drug-tolerant persister cells in HGSOC

Kathrin Böpple; Yaara Oren; Whitney S. Henry; Meng Dong; Sandra Weller; Julia Thiel; Markus Kleih; Andrea Gaißler; Damaris Zipperer; Hans Georg Kopp; Yael Aylon; Moshe Oren; Frank Essmann; Chunguang Liang; Walter E. Aulitzky

doi:10.1038/s41419-024-06674-x

ATF3 characterizes aggressive drug-tolerant persister cells in HGSOC

Kathrin Böpple^*, Yaara Oren, Whitney S. Henry, Meng Dong, Sandra Weller, Julia Thiel, Markus Kleih, Andrea Gaißler, Damaris Zipperer, Hans Georg Kopp, Yael Aylon, Moshe Oren, Frank Essmann, Chunguang Liang^*, Walter E. Aulitzky

^*Corresponding author for this work

Department of Molecular Cell Biology

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	290
Journal	Cell Death and Disease
Volume	15
DOIs	https://doi.org/10.1038/s41419-024-06674-x
Publication status	Published - 24 Apr 2024

Bibliographical note

Special thanks to Kerstin Willecke, Jutta Bader and Sonja Lude for excellent technical assistance and Ferenc Reinhard for support in the animal experiments. We would like to thank Prof. Roland E. Kontermann and Prof. Aviv Regev for scientific support of this work. The results shown here are in part based upon data generated by the TCGA Research Network. We would like to thank The Cancer Genome Atlas initiative, all tissue donors, and investigators who contributed to the acquisition and analyses of the samples used in this study. This manuscript is dedicated to the memory of Dr. Heiko van der Kuip.
The study was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and the Berthold Leibinger Stiftung (Ditzingen, Germany) (WEA and MO), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) TRR 221/INF (CL) and by the Rising Tide Foundation (MO). WSH was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund and YO was supported by the Hope Fund for Cancer Research Postdoctoral Fellowship, The Azrieli Faculty Scholars program and the Rivkin Scientific Scholar Award.

Publisher Copyright:
© The Author(s) 2024.

All Science Journal Classification (ASJC) codes

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

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10.1038/s41419-024-06674-xLicence: CC BY

Cite this

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title = "ATF3 characterizes aggressive drug-tolerant persister cells in HGSOC",

abstract = "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-na{\"i}ve 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.",

author = "Kathrin B{\"o}pple and Yaara Oren and Henry, {Whitney S.} and Meng Dong and Sandra Weller and Julia Thiel and Markus Kleih and Andrea Gai{\ss}ler and Damaris Zipperer and Kopp, {Hans Georg} and Yael Aylon and Moshe Oren and Frank Essmann and Chunguang Liang and Aulitzky, {Walter E.}",

note = "Special thanks to Kerstin Willecke, Jutta Bader and Sonja Lude for excellent technical assistance and Ferenc Reinhard for support in the animal experiments. We would like to thank Prof. Roland E. Kontermann and Prof. Aviv Regev for scientific support of this work. The results shown here are in part based upon data generated by the TCGA Research Network. We would like to thank The Cancer Genome Atlas initiative, all tissue donors, and investigators who contributed to the acquisition and analyses of the samples used in this study. This manuscript is dedicated to the memory of Dr. Heiko van der Kuip. The study was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and the Berthold Leibinger Stiftung (Ditzingen, Germany) (WEA and MO), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) TRR 221/INF (CL) and by the Rising Tide Foundation (MO). WSH was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund and YO was supported by the Hope Fund for Cancer Research Postdoctoral Fellowship, The Azrieli Faculty Scholars program and the Rivkin Scientific Scholar Award. Publisher Copyright: {\textcopyright} The Author(s) 2024.",

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doi = "10.1038/s41419-024-06674-x",

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T1 - ATF3 characterizes aggressive drug-tolerant persister cells in HGSOC

AU - Böpple, Kathrin

AU - Oren, Yaara

AU - Henry, Whitney S.

AU - Dong, Meng

AU - Weller, Sandra

AU - Thiel, Julia

AU - Kleih, Markus

AU - Gaißler, Andrea

AU - Zipperer, Damaris

AU - Kopp, Hans Georg

AU - Aylon, Yael

AU - Oren, Moshe

AU - Essmann, Frank

AU - Liang, Chunguang

AU - Aulitzky, Walter E.

N1 - Special thanks to Kerstin Willecke, Jutta Bader and Sonja Lude for excellent technical assistance and Ferenc Reinhard for support in the animal experiments. We would like to thank Prof. Roland E. Kontermann and Prof. Aviv Regev for scientific support of this work. The results shown here are in part based upon data generated by the TCGA Research Network. We would like to thank The Cancer Genome Atlas initiative, all tissue donors, and investigators who contributed to the acquisition and analyses of the samples used in this study. This manuscript is dedicated to the memory of Dr. Heiko van der Kuip. The study was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and the Berthold Leibinger Stiftung (Ditzingen, Germany) (WEA and MO), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) TRR 221/INF (CL) and by the Rising Tide Foundation (MO). WSH was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund and YO was supported by the Hope Fund for Cancer Research Postdoctoral Fellowship, The Azrieli Faculty Scholars program and the Rivkin Scientific Scholar Award. Publisher Copyright: © The Author(s) 2024.

PY - 2024/4/24

Y1 - 2024/4/24

N2 - 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.

AB - 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.

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ER -

ATF3 characterizes aggressive drug-tolerant persister cells in HGSOC

Abstract

Bibliographical note

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