CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo
Abstract Epithelial ovarian cancer (EOC) metastasizes predominantly through multicellular aggregates known as spheroids, which disseminate within the peritoneal cavity and initiate secondary disease upon reattachment at distant sites. EOC spheroids resist detachment-induced cell death by upregulatin...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-11584-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849763509629353984 |
|---|---|
| author | Matthew J. Borrelli Adrian Buensuceso Yudith Ramos Valdes Tiffany P.A. Johnston Jacob Haagsma Trevor G. Shepherd |
| author_facet | Matthew J. Borrelli Adrian Buensuceso Yudith Ramos Valdes Tiffany P.A. Johnston Jacob Haagsma Trevor G. Shepherd |
| author_sort | Matthew J. Borrelli |
| collection | DOAJ |
| description | Abstract Epithelial ovarian cancer (EOC) metastasizes predominantly through multicellular aggregates known as spheroids, which disseminate within the peritoneal cavity and initiate secondary disease upon reattachment at distant sites. EOC spheroids resist detachment-induced cell death by upregulating stress responses including AMP-activated protein kinase (AMPK) signaling and AMPK-dependent macroautophagy (autophagy), highlighting these pathways as potential therapeutic targets. Previously, we used a pharmacological approach to putatively identify Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKKβ, encoded by CAMKK2) as the primary activator of AMPK in EOC spheroids. Herein we have generated CAMKK2 knockout EOC cell lines via CRISPR–Cas9 genome editing to confirm this function of CAMKKβ and explore the impacts of its loss using in vitro and in vivo models of metastatic EOC. CAMKK2 knockout spheroids exhibited decreased AMPK activation, autophagic flux, cell viability, and metastatic potential relative to parental spheroids, and intraperitoneal xenograft tumours lacking CAMKKβ grew slower than their CAMKKβ-intact counterparts. Effect magnitudes varied between cell line models, suggesting context-dependent roles for CAMKKβ in EOC and rationalizing further studies to characterize the underlying mechanisms. Altogether, our findings highlight CAMKKβ as an important contributor to metabolic reprogramming in EOC spheroids and as a potential therapeutic target in the setting of advanced disease. |
| format | Article |
| id | doaj-art-be8c2a553974454fbfa1be8b7c176fdb |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-be8c2a553974454fbfa1be8b7c176fdb2025-08-20T03:05:23ZengNature PortfolioScientific Reports2045-23222025-07-0115111310.1038/s41598-025-11584-9CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivoMatthew J. Borrelli0Adrian Buensuceso1Yudith Ramos Valdes2Tiffany P.A. Johnston3Jacob Haagsma4Trevor G. Shepherd5The Mary and John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer CentreThe Mary and John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer CentreThe Mary and John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer CentreThe Mary and John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer CentreThe Mary and John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer CentreThe Mary and John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer CentreAbstract Epithelial ovarian cancer (EOC) metastasizes predominantly through multicellular aggregates known as spheroids, which disseminate within the peritoneal cavity and initiate secondary disease upon reattachment at distant sites. EOC spheroids resist detachment-induced cell death by upregulating stress responses including AMP-activated protein kinase (AMPK) signaling and AMPK-dependent macroautophagy (autophagy), highlighting these pathways as potential therapeutic targets. Previously, we used a pharmacological approach to putatively identify Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKKβ, encoded by CAMKK2) as the primary activator of AMPK in EOC spheroids. Herein we have generated CAMKK2 knockout EOC cell lines via CRISPR–Cas9 genome editing to confirm this function of CAMKKβ and explore the impacts of its loss using in vitro and in vivo models of metastatic EOC. CAMKK2 knockout spheroids exhibited decreased AMPK activation, autophagic flux, cell viability, and metastatic potential relative to parental spheroids, and intraperitoneal xenograft tumours lacking CAMKKβ grew slower than their CAMKKβ-intact counterparts. Effect magnitudes varied between cell line models, suggesting context-dependent roles for CAMKKβ in EOC and rationalizing further studies to characterize the underlying mechanisms. Altogether, our findings highlight CAMKKβ as an important contributor to metabolic reprogramming in EOC spheroids and as a potential therapeutic target in the setting of advanced disease.https://doi.org/10.1038/s41598-025-11584-9Epithelial ovarian cancerSpheroidMetastasisCAMKK2AMPKAutophagy |
| spellingShingle | Matthew J. Borrelli Adrian Buensuceso Yudith Ramos Valdes Tiffany P.A. Johnston Jacob Haagsma Trevor G. Shepherd CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo Scientific Reports Epithelial ovarian cancer Spheroid Metastasis CAMKK2 AMPK Autophagy |
| title | CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo |
| title_full | CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo |
| title_fullStr | CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo |
| title_full_unstemmed | CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo |
| title_short | CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo |
| title_sort | camkkβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo |
| topic | Epithelial ovarian cancer Spheroid Metastasis CAMKK2 AMPK Autophagy |
| url | https://doi.org/10.1038/s41598-025-11584-9 |
| work_keys_str_mv | AT matthewjborrelli camkkbsupportsgrowthandviabilityofepithelialovariancancerinvitroandinvivo AT adrianbuensuceso camkkbsupportsgrowthandviabilityofepithelialovariancancerinvitroandinvivo AT yudithramosvaldes camkkbsupportsgrowthandviabilityofepithelialovariancancerinvitroandinvivo AT tiffanypajohnston camkkbsupportsgrowthandviabilityofepithelialovariancancerinvitroandinvivo AT jacobhaagsma camkkbsupportsgrowthandviabilityofepithelialovariancancerinvitroandinvivo AT trevorgshepherd camkkbsupportsgrowthandviabilityofepithelialovariancancerinvitroandinvivo |