In high-grade ovarian carcinoma, platinum-sensitive tumor recurrence and acquired-resistance derive from quiescent residual cancer cells that overexpress CRYAB, CEACAM6, and SOX2
Corresponding Author
Stanislas du Manoir
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Correspondence to: S du Manoir or C Theillet, IRCM U1194, INSERM, University of Montpellier, ICM, 208, rue des Apothicaires, F-34298 Montpellier, Cedex 5, Montpellier, France. E-mail: [email protected] (S du Manoir) or [email protected] (C Theillet)
Search for more papers by this authorHélène Delpech
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorBéatrice Orsetti
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorWilliam Jacot
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorNelly Pirot
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorJean Noel
BCM, University of Montpellier, CNRS, INSERM, Montpellier, France
Search for more papers by this authorPierre-Emmanuel Colombo
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorClaude Sardet
IRCM U1194, INSERM, University of Montpellier, ICM, CNRS, Montpellier, France
Search for more papers by this authorCorresponding Author
Charles Theillet
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Correspondence to: S du Manoir or C Theillet, IRCM U1194, INSERM, University of Montpellier, ICM, 208, rue des Apothicaires, F-34298 Montpellier, Cedex 5, Montpellier, France. E-mail: [email protected] (S du Manoir) or [email protected] (C Theillet)
Search for more papers by this authorCorresponding Author
Stanislas du Manoir
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Correspondence to: S du Manoir or C Theillet, IRCM U1194, INSERM, University of Montpellier, ICM, 208, rue des Apothicaires, F-34298 Montpellier, Cedex 5, Montpellier, France. E-mail: [email protected] (S du Manoir) or [email protected] (C Theillet)
Search for more papers by this authorHélène Delpech
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorBéatrice Orsetti
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorWilliam Jacot
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorNelly Pirot
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorJean Noel
BCM, University of Montpellier, CNRS, INSERM, Montpellier, France
Search for more papers by this authorPierre-Emmanuel Colombo
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Search for more papers by this authorClaude Sardet
IRCM U1194, INSERM, University of Montpellier, ICM, CNRS, Montpellier, France
Search for more papers by this authorCorresponding Author
Charles Theillet
IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France
Correspondence to: S du Manoir or C Theillet, IRCM U1194, INSERM, University of Montpellier, ICM, 208, rue des Apothicaires, F-34298 Montpellier, Cedex 5, Montpellier, France. E-mail: [email protected] (S du Manoir) or [email protected] (C Theillet)
Search for more papers by this authorNo conflicts of interest were declared.
Abstract
Most high-grade ovarian carcinomas (HGOCs) are sensitive to carboplatin (CBP)-based chemotherapy but frequently recur within 24 months. Recurrent tumors remain CBP-sensitive and acquire resistance only after several treatment rounds. Recurrences arise from a small number of residual tumor cells not amenable to investigation in patients. We developed patient-derived xenografts (PDXs) that allow the study of these different stages of CBP-sensitive recurrence and acquisition of resistance. We generated PDX models from CBP-sensitive and intrinsically resistant HGOC. PDXs were CBP- or mock-treated and tumors were sampled, after treatment and at recurrence. We also isolated models with acquired-resistance from CBP-sensitive PDXs. Tumors were characterized at the histological and transcriptome levels. PDX models reproduced treatment response seen in the patients. CBP-sensitive residual tumors contained nonproliferating tumor cell clusters embedded in a fibrotic mesh. In nontreated PDX tumors and treated CBP-resistant tumors, fibrotic tissue was not prevalent. Residual tumors had marked differences in gene expression when compared to naïve and recurrent tumors, indicating downregulation of the cell cycle and proliferation and upregulation of interferon response and the epithelial–mesenchymal transition. This gene expression pattern resembled that described in embryonal diapause and ‘drug-tolerant persister’ states. Residual and acquired-resistance tumors share the overexpression of three genes: CEACAM6, CRYAB, and SOX2. Immunostaining analysis showed strong CEACAM6, CRYAB, and SOX2 protein expression in CBP-sensitive residual and acquired-resistance PDX, thus confirming the RNA profiling results. In HGOC PDX, CBP-sensitive recurrences arise from a small population of quiescent, drug-tolerant, residual cells embedded in a fibrotic mesh. These cells overexpress CEACAM6, CRYAB, and SOX2, whose overexpression is also associated with acquired resistance and poor patient prognosis. CEACAM6, CRYAB, and SOX2 may thus serve as a biomarker to predict recurrence and emergence of resistant disease in CBP-treated HGOC patients. © 2022 The Pathological Society of Great Britain and Ireland.
Open Research
Data availability statement
All expression profiling data are publicly available under GSE198701 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE198701).
Supporting Information
Filename | Description |
---|---|
path5896-sup-0001-SuppMatMeth,FiguresS1-S10,TableS1.pdfPDF document, 4.2 MB | Supplementary materials and methods Figure S1. Evolution of tumor volumes in the 10 PDX models during treatment (50 mg/Kg, twice per week, 4 weeks) Figure S2. Percentage of Ki-67 positive nuclei in the tested PDXs Figure S3. Representative cleaved caspase-3 immunostaining in two PDX models Figure S4. CBP-sens PDX regress under treatment with a massive fibrosis build up Figure S5. Modified pathways and annotation of the genes overexpressed in residual PDX Figure S6. Principal pathways modified in posttreatment residual HGPC PDX. Figure S7. HGOC expressing high levels of CEACAM6 or CRYAB or SOX2 recur earlier than those with low levels Figure S8. Representative immunostaining for PAX8, CEACAM6, CRYAB and SOX2 Figure S9. CEACAM6, CRYAB and SOX2 immunostaining in nontreated PDX models used in this study Figure S10. CEACAM6, CRYAB, SOX2 immunostaining patterns in patient tumor O3312 Table S1. Essential clinical information of the primary High Grade Ovarian Carcinomas from which the PDX models used in this study were derived |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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