<p dir="ltr">PDAC, the most common type of pancreatic cancer, is a highly metastatic cancer that has a low survival rate. It is histologically characterized by a thick desmoplastic stroma. Counterintuitively, PCCs can still manage to survive in such a restrictive environment and even metastasize to distant organs. Over the years, efforts have been made to find out the mechanisms underlying these perplexing behaviors. However, questions about the role of ECM accumulation and enhanced stiffness in PCC dissemination remained unanswered. In this dissertation, we aim to advance the material design for tumor modeling, and propose an explanation for the malignant cell behavior in the PDAC TME. This is achieved through the use of hydrogel-based tumor models that recapitulate the elevated stiffness of the tumor tissue. Specifically, hydrogel stiffness was tuned to mimic the PDAC TME to understand how PCCs and CAFs respond to various substrate stiffnesses temporally. Next, we employ bio-orthogonal click chemistries to create hydrogels with on-demand stiffening capabilities, as well as hyaluronic acid deposition in the hydrogel, to investigate the effect of dynamic change in matrix stiffness and composition on PDAC cells and CAFs. Lastly, by leveraging thiol-norbornene, aldehyde-hydrazide, and tetrazine-norbornene click chemistries, we created a microporous hydrogel system with a conformation that combines both the advantage of 3D cell culture and the non-restricting nature of 2D cell culture. Additionally, the system allows the application of modularized user-defined factors, including, but not limited to stiffness and HA deposition to the system. Stiff gel in 2D facilitated cell spreading of Pa03C in the presence of CAF. Despite being more restrictive on cell spreading, stiff gelatin gel in 3D induced cytokines that promote matrix remodeling and spreading cell morphology can be restored by stiffening with HA. Overall, this dissertation demonstrated that ECM component (i.e., HA), culture dimensionality, and cell-cell interaction play a huge role in cell behavior, and these factors may interact with each other and result in synergistic effects.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/26364730 |
| Date | 27 July 2024 |
| Creators | Chun-Yi Chang (19207171) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/DEVELOPMENT_OF_CLICK_HYDROGEL_MODELS_TO_STUDY_PANCREATIC_CANCER_CELL_FATE/26364730 |
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