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Mitochondrial plasticity supports proliferative outgrowth and invasion of ovarian cancer spheroids during adhesion

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dc.contributor.authorGrieco, Joseph P.en
dc.contributor.authorCompton, Stephanie L. E.en
dc.contributor.authorBano, Naziaen
dc.contributor.authorBrookover, Lucyen
dc.contributor.authorNichenko, Anna S.en
dc.contributor.authorDrake, Joshua C.en
dc.contributor.authorSchmelz, Eva M.en
dc.date.accessioned2023-02-20T18:01:38Zen
dc.date.available2023-02-20T18:01:38Zen
dc.date.issued2023-01-16en
dc.date.updated2023-02-20T15:06:21Zen
dc.description.abstractBackground: Ovarian cancer cells aggregate during or after exfoliation from the primary tumor to form threedimensional spheroids. Spheroid formation provides a survival advantage during peritoneal dissemination in nutrient and oxygen-depleted conditions which is accompanied by a suppressed metabolic phenotype and fragmented mitochondria. Upon arrival to their metastatic sites, spheroids adhere to peritoneal organs and transition to a more epithelial phenotype to support outgrowth and invasion. In this study, we investigated the plasticity of mitochondrial morphology, dynamics, and function upon adhesion. Methods: Using our slow-developing (MOSE-L) and fast-developing (MOSE-LTICv) ovarian cancer models, we mimicked adhesion and reoxygenation conditions by plating the spheroids onto tissue culture dishes and changing culture conditions from hypoxia and low glucose to normoxia with high glucose levels after adhesion. We used Western Blot, microscopy and Seahorse analyses to determine the plasticity of mitochondrial morphology and functions upon adhesion, and the impact on proliferation and invasion capacities. Results: Independent of culture conditions, all spheroids adhered to and began to grow onto the culture plates. While the bulk of the spheroid was unresponsive, the mitochondrial morphology in the outgrowing cells was indistinguishable from cells growing in monolayers, indicating that mitochondrial fragmentation in spheroids was indeed reversible. This was accompanied by an increase in regulators of mitobiogenesis, PGC1a, mitochondrial mass, and respiration. Reoxygenation increased migration and invasion in both cell types but only the MOSE-L responded with increased proliferation to reoxygenation. The highly aggressive phenotype of the MOSE-LTICv was characterized by a relative independence of oxygen and the preservation of higher levels of proliferation, migration and invasion even in limiting culture conditions but a higher reliance on mitophagy. Further, the outgrowth in these aggressive cells relies mostly on proliferation while the MOSE-L cells both utilize proliferation and migration to achieve outgrowth. Suppression of proliferation with cycloheximide impeded aggregation, reduced outgrowth and invasion via repression of MMP2 expression and the flattening of the spheroids. Discussion: Our studies indicate that the fragmentation of the mitochondria is reversible upon adhesion. The identification of regulatory signaling molecules and pathways of these key phenotypic alterations that occur during primary adhesion and invasion is critical for the identification of druggable targets for therapeutic intervention to prevent aggressive metastatic disease.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fonc.2022.1043670en
dc.identifier.eissn2234-943Xen
dc.identifier.issn2234-943Xen
dc.identifier.orcidSchmelz, Eva [0000-0002-3374-5266]en
dc.identifier.orcidDrake, Joshua [0000-0001-6658-4975]en
dc.identifier.otherPMC9884807en
dc.identifier.pmid36727073en
dc.identifier.urihttp://hdl.handle.net/10919/113878en
dc.identifier.volume12en
dc.language.isoenen
dc.publisherFrontiersen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36727073en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectadhesionen
dc.subjectcycloheximideen
dc.subjectmitobiogenesisen
dc.subjectmitochondriaen
dc.subjectmitophagyen
dc.subjectovarian cancer metabolismen
dc.subjectreoxygenationen
dc.subjectspheroiden
dc.subjectBiotechnologyen
dc.subjectRare Diseasesen
dc.subjectOvarian Canceren
dc.subjectCanceren
dc.titleMitochondrial plasticity supports proliferative outgrowth and invasion of ovarian cancer spheroids during adhesionen
dc.title.serialFrontiers in Oncologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherJournal Articleen
dcterms.dateAccepted2022-12-19en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Human Nutrition, Foods, & Exerciseen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen

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