Journal article 32 views 12 downloads
Adipocyte Derived Exosomes Promote Cell Invasion and Challenge Paclitaxel Efficacy in Ovarian Cancer
,
Steve Conlan ,
Francesca Taraballi,
Deya Gonzalez
Cell Communication and Signaling
Swansea University Authors:
David Howard, Claire Donnelly, Jezabel Garcia Parra, Meg Pugh, KADIE EDWARDS, Lewis Francis , Steve Conlan , Deya Gonzalez
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DOI (Published version): 10.1186/s12964-024-01806-4
Abstract
Background: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in pr...
| Published in: | Cell Communication and Signaling |
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| Published: |
Springer
2024
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa67596 |
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| Abstract: |
Background: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. Methods: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. Results: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells.Conclusions: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies. |
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| Keywords: |
Ovarian cancer, Omentum, Adipocytes, Exosomes, miRNA, Mir-21, Prolactin, Obesity |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
The project was funded by Health Care Research Wales (HCRW) studentship grant HS-16-38, the Medical Research Council UK Confidence in Concept grant (MC_PC_19053), the Medical Research Council UK Impact Acceleration Account grant (MR/X502686/1). Welsh Government ERDF SMART Expertise 2014–2022 West Wales and the Valleys grants (2017/COL/001 and 2017/COL/004), and Swansea University Texas academic partnership PhD programme. |