Phenotypic heterogeneity driven by cell-cell signaling: principles of pattern formation and implications for metastasis
| dc.contributor.advisor | Onuchic, José Nelson | |
| dc.creator | Bocci, Federico | |
| dc.date.accessioned | 2019-12-03T14:00:19Z | |
| dc.date.available | 2019-12-03T14:00:19Z | |
| dc.date.created | 2019-12 | |
| dc.date.issued | 2019-12-02 | |
| dc.date.submitted | December 2019 | |
| dc.date.updated | 2019-12-03T14:00:20Z | |
| dc.description.abstract | Non-genetic heterogeneity pervades biological systems such as bacterial colonies, tissues in physiological conditions as well as diseases such as cancer. The presence of different cell phenotype can be facilitated by mechanisms of communication between cells. Interesting examples include pairwise interactions between neighboring cells as well as long-range communication over several cell diameters guided by signaling gradients. Here, we use theoretical and computational modeling to address the role of cell-cell communication through the Notch signaling pathway in guiding cell differentiation and promoting phenotypic heterogeneity in a cell population. Notch signaling is an evolutionary conserved signaling mechanism that enables communication between nearest neighbors. This pathway can guide neighboring cells to assume opposite phenotypes (lateral inhibition) or similar phenotypes (lateral induction) and has been implicated in several aspects of cancer progression, including cell migration, proliferation and resistance to therapies. With the help of dynamical modeling, we elucidate the operating principles of cellular patterning mediated by Notch. This model predicts a transition from lateral inhibition to lateral induction that helps rationalize endothelial cell differentiation during blood vessel development. Moreover, we extend this theoretical framework to investigate the implications of Notch signaling in the context of cancer metastasis. To achieve this framework, we model the interconnections between Notch and other signaling pathways implicated in cancer invasion, including the Epithelial-Mesenchymal Transition (EMT) and the acquisition of cancer stem cell (CSC) traits. Notch can promote a ‘window of aggressiveness’ where cells acquire a highly metastatic phenotype characterized by a partial EMT and stem-like traits. Moreover, this model, in concerto with experimental investigations, identifies molecular perturbations that destabilize aggressive cancer phenotypes, hence proposing potential therapeutic targets to alleviate the metastatic load. To take a further step toward coupling biochemical regulation and biophysics of cancer cell migration, we further develop a coarse-grained model that connects intra- tumoral heterogeneity driven by the Epithelial-Mesenchymal Transition with the invasion strategy of cancer cells. This framework is predictive of the different invasion modes of cancer cells, including single and collective cell migration, when validated against experimental datasets across cancer types. Finally, we investigate the spatial separation of different bacterial populations driven by the diffusion of nutrients inside a bacterial colony. Differently from Notch signaling, this mechanism of cell differentiation operates on the scale of a cell population and offers an interesting parallel to cancer stem cell patterning observed in vivo. Overall, the work proposed continues to unravel the principles of cell fate determination, patterning and behavior guided by the communication of a cell with neighboring cells and the extracellular environment. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.citation | Bocci, Federico. "Phenotypic heterogeneity driven by cell-cell signaling: principles of pattern formation and implications for metastasis." (2019) Diss., Rice University. <a href="https://hdl.handle.net/1911/107752">https://hdl.handle.net/1911/107752</a>. | |
| dc.identifier.uri | https://hdl.handle.net/1911/107752 | |
| dc.language.iso | eng | |
| dc.rights | Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder. | |
| dc.subject | heterogeneity | |
| dc.subject | signaling Notch | |
| dc.subject | epithelial-mesenchymal transition | |
| dc.title | Phenotypic heterogeneity driven by cell-cell signaling: principles of pattern formation and implications for metastasis | |
| dc.type | Thesis | |
| dc.type.material | Text | |
| thesis.degree.department | Chemistry | |
| thesis.degree.discipline | Natural Sciences | |
| thesis.degree.grantor | Rice University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy |
Files
Original bundle
1 - 1 of 1