Biomaterials-based models of adult and pediatric brain cancer elucidate the role of cell-matrix interactions
Abstract/Contents
- Abstract
- Adult and pediatric brain cancers reside in complex 3D microenvironments and are constantly subjected to a spectrum of mechanical and biochemical cues from the surrounding extracellular matrix (ECM). Cells sense and respond to these niche cues, and this interplay plays a critical role in regulating tumor progression. For instance, despite being mechanically confined by the 3D microenvironment, cancer cells are notoriously invasive and can rapidly overcome physical barriers. This requires cancer cells to engage mechanotransductive pathways to adapt, generate, and transmit biophysical forces to overcome the surrounding mechanical constraints. Moreover, these ECM niche properties have also been found to influence aggressive cancer cell phenotype and response to standard-of-care therapy regiments. While recent advancements have revealed the importance of niche cues in driving tumor progression, this field is still in its infancy especially for these aggressive brain cancers. My thesis work aims to investigate how mechanical properties of the tumor niche such as matrix viscoelasticity and stiffness regulate adult Glioblastoma Multiforme (GBM) invasive behavior and chemoradiotherapy response. Specifically, through the development of an engineered and tunable 3D biomaterials-based hydrogel model, I show that adult derived GBM cells are sensitive to matrix viscoelasticity and stiffness cues present within the tumor niche. Moreover, I identify and validate biophysical mechanisms mediating aggressive behavior via both cytoskeletal and nuclear mechanotransduction pathways in response to brain-mimicking mechanical cues. Additionally, I have worked to uncover the role of ECM ligands and their associated integrin receptors on invasion and treatment response for a rare but devasting pediatric brain cancer known as Diffuse Intrinsic Pontine Glioma (DIPG). By leveraging human induced pluripotent stem cell-derived neural organoids as a model system, I demonstrate that laminin associated integrin knockdown dampens DIPG invasion and improves therapy response. Ultimately, this thesis work elucidates novel biophysical mechanisms driving key brain cancer processes and identifies potential strategies to improve current treatment regimens.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2024 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Sinha, Sauradeep |
|---|---|
| Degree supervisor | Yang, Fan, (Bioengineering researcher and teacher) |
| Thesis advisor | Yang, Fan, (Bioengineering researcher and teacher) |
| Thesis advisor | Chaudhuri, Ovijit |
| Thesis advisor | Grant, Gerald (Gerald A.) |
| Thesis advisor | Heilshorn, Sarah |
| Degree committee member | Chaudhuri, Ovijit |
| Degree committee member | Grant, Gerald (Gerald A.) |
| Degree committee member | Heilshorn, Sarah |
| Associated with | Stanford University, School of Engineering |
| Associated with | Stanford University, Department of Bioengineering |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Sauradeep Sinha. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis Ph.D. Stanford University 2024. |
| Location | https://purl.stanford.edu/xz336gm7226 |
Access conditions
- Copyright
- © 2023 by Sauradeep Sinha
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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