Patient‐derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways
Malignant ascites is commonly produced in advanced epithelial ovarian cancer (EOC) and serves as unique microenvironment for tumour cells. Acellular ascites fluid (AAF) is rich in signalling molecules and has been proposed to play a role in the induction of chemoresistance. Through in vitro testing...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13726 |
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| author | Katharina Bischof Andrea Cremaschi Lena Eroukhmanoff Johannes Landskron Lise‐Lotte Flage‐Larsen Alexandra Gade Line Bjørge Alfonso Urbanucci Kjetil Taskén |
| author_facet | Katharina Bischof Andrea Cremaschi Lena Eroukhmanoff Johannes Landskron Lise‐Lotte Flage‐Larsen Alexandra Gade Line Bjørge Alfonso Urbanucci Kjetil Taskén |
| author_sort | Katharina Bischof |
| collection | DOAJ |
| description | Malignant ascites is commonly produced in advanced epithelial ovarian cancer (EOC) and serves as unique microenvironment for tumour cells. Acellular ascites fluid (AAF) is rich in signalling molecules and has been proposed to play a role in the induction of chemoresistance. Through in vitro testing of drug sensitivity and by assessing intracellular phosphorylation status in response to mono‐ and combination treatment of five EOC cell lines after incubation with AAFs derived from 20 different patients, we investigated the chemoresistance‐inducing potential of ascites. We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard‐of‐care drugs (SCDs). We also show that AAFs induce time‐ and concentration‐dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen‐activated protein kinase kinase (MEK), phosphoinositide 3‐kinase (PI3K)–protein kinase B (AKT) and nuclear factor NF‐kappa‐B (NFκB). Antibodies targeting the interleukin‐6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1. Treatments with SCDs were effective in reducing cell viability in only a third of 30 clinically relevant conditions examined, defined as combinations of drugs, different cell lines and AAFs. Combinations of SCDs and novel therapeutics such as trametinib, fludarabine or rapamycin were superior in another third. Notably, we could nominate effective treatment combinations in almost all conditions except in 4 out of 30 conditions, in which trametinib or fludarabine showed higher efficacy alone. Taken together, our study underscores the importance of the molecular characterisation of individual patients' AAFs and the impact on treatment resistance as providing clinically meaningful information for future precision treatment approaches in EOC. |
| format | Article |
| id | doaj-art-9d0dbc2ad4ee4484b8a94bce96f2f6bc |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-9d0dbc2ad4ee4484b8a94bce96f2f6bc2025-01-07T14:42:32ZengWileyMolecular Oncology1574-78911878-02612025-01-01191819810.1002/1878-0261.13726Patient‐derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathwaysKatharina Bischof0Andrea Cremaschi1Lena Eroukhmanoff2Johannes Landskron3Lise‐Lotte Flage‐Larsen4Alexandra Gade5Line Bjørge6Alfonso Urbanucci7Kjetil Taskén8Department of Cancer Immunology, Institute for Cancer Research University of Oslo NorwayCentre for Molecular Medicine Norway (NCMM) Nordic EMBL Partnership, University of Oslo NorwayCentre for Molecular Medicine Norway (NCMM) Nordic EMBL Partnership, University of Oslo NorwayCentre for Molecular Medicine Norway (NCMM) Nordic EMBL Partnership, University of Oslo NorwayCentre for Molecular Medicine Norway (NCMM) Nordic EMBL Partnership, University of Oslo NorwayCentre for Molecular Medicine Norway (NCMM) Nordic EMBL Partnership, University of Oslo NorwayDepartment of Obstetrics and Gynaecology Haukeland University Hospital Bergen NorwayFaculty of Medicine and Health Technology TAYS Cancer Centre and FICAN Mid, Tampere University FinlandDepartment of Cancer Immunology, Institute for Cancer Research University of Oslo NorwayMalignant ascites is commonly produced in advanced epithelial ovarian cancer (EOC) and serves as unique microenvironment for tumour cells. Acellular ascites fluid (AAF) is rich in signalling molecules and has been proposed to play a role in the induction of chemoresistance. Through in vitro testing of drug sensitivity and by assessing intracellular phosphorylation status in response to mono‐ and combination treatment of five EOC cell lines after incubation with AAFs derived from 20 different patients, we investigated the chemoresistance‐inducing potential of ascites. We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard‐of‐care drugs (SCDs). We also show that AAFs induce time‐ and concentration‐dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen‐activated protein kinase kinase (MEK), phosphoinositide 3‐kinase (PI3K)–protein kinase B (AKT) and nuclear factor NF‐kappa‐B (NFκB). Antibodies targeting the interleukin‐6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1. Treatments with SCDs were effective in reducing cell viability in only a third of 30 clinically relevant conditions examined, defined as combinations of drugs, different cell lines and AAFs. Combinations of SCDs and novel therapeutics such as trametinib, fludarabine or rapamycin were superior in another third. Notably, we could nominate effective treatment combinations in almost all conditions except in 4 out of 30 conditions, in which trametinib or fludarabine showed higher efficacy alone. Taken together, our study underscores the importance of the molecular characterisation of individual patients' AAFs and the impact on treatment resistance as providing clinically meaningful information for future precision treatment approaches in EOC.https://doi.org/10.1002/1878-0261.13726asciteschemoresistancedrug sensitivityintracellular signallingovarian cancerphospho flow |
| spellingShingle | Katharina Bischof Andrea Cremaschi Lena Eroukhmanoff Johannes Landskron Lise‐Lotte Flage‐Larsen Alexandra Gade Line Bjørge Alfonso Urbanucci Kjetil Taskén Patient‐derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways Molecular Oncology ascites chemoresistance drug sensitivity intracellular signalling ovarian cancer phospho flow |
| title | Patient‐derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways |
| title_full | Patient‐derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways |
| title_fullStr | Patient‐derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways |
| title_full_unstemmed | Patient‐derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways |
| title_short | Patient‐derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways |
| title_sort | patient derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways |
| topic | ascites chemoresistance drug sensitivity intracellular signalling ovarian cancer phospho flow |
| url | https://doi.org/10.1002/1878-0261.13726 |
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