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Bioenergetic regulation of metastatic cell migration and tumor angiogenesis by matrix mechanics

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dc.contributor.authorZanotelli, Matthew R.
dc.contributor.chairKing, Cynthia A.
dc.contributor.committeeMemberCerione, Richard A.
dc.contributor.committeeMemberPutnam, David A.
dc.contributor.committeeMemberSpector, Jason Adam
dc.date.accessioned2021-09-09T17:41:11Z
dc.date.available2023-06-09T06:00:33Z
dc.date.issued2021-05
dc.description278 pages
dc.description.abstractCell migration during many fundamental biological processes including metastasis and angiogenesis requires cells to traverse tissue with heterogeneous biophysical cues. During the invasion-metastasis cascade, cancer cells must navigate a structurally and mechanically complex microenvironment that significantly impacts behavior and directs migrating cells. While significant research has been performed to understand the cellular and molecular mechanisms guiding migration, less is understood about bioenergetic regulation and metabolism during migration. Here, I utilize in vitro models of the tumor-associated matrix to study the effect of mechanical cues on energetic costs associated with migration and their influence on motility. In high density collagen, where migration is impaired, intracellular bioenergetics increased and energy state decreased in aligned collagen matrices, where migration is facilitated. Motility in confined collagen microtracks impose high energetic demands on migrating cells and cells migrate in the direction that minimizes energetic costs. The pro-invasive cues collagen fiber alignment and fiber tension were next decoupled to study their individual impact on migration. Applying tension perpendicular to fiber alignment increases potential energy stored within collagen fibers, lowering requirements for cell-induced matrix deformation and energy usage during migration compared to motility in the direction of fiber alignment. Collagen density and pore size were then altered to change the level of physical constraint on migrating cells and individual cells were sorted based on their level of migration. The metabolic activity of each gel reflected the number of motile cells present and energetics were only a function of matrix properties for highly motile cells, not cells with low motility. Conditions most permissive to migration required less energy usage during movement, indicating efficient migration facilitates increased motility. Energy costs associated with migration were also demonstrated to play a role in determining endothelial cell phenotype during angiogenic sprouting. Tip cell lifetime decreased with increasing collagen density, as tip cells required more energy compared to stalk cells and this difference increased with increasing density. Together, this work provides a conceptual understanding of how mechanical cues influence bioenergetics during migration and demonstrates energy minimalization directs migration.
dc.identifier.doihttps://doi.org/10.7298/ctcj-mw86
dc.identifier.otherZanotelli_cornellgrad_0058F_12498
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:12498
dc.identifier.urihttps://hdl.handle.net/1813/109827
dc.language.isoen
dc.subjectangiogenesis
dc.subjectcancer
dc.subjectcell migration
dc.subjectextracellular matrix
dc.subjectmechanobiology
dc.subjectmetabolism
dc.titleBioenergetic regulation of metastatic cell migration and tumor angiogenesis by matrix mechanics
dc.typedissertation or thesis
dcterms.licensehttps://hdl.handle.net/1813/59810
thesis.degree.disciplineBiomedical Engineering
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Biomedical Engineering

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