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Reprogramming the Pancreatic Cancer Stroma by Targeting Coagulation at the Tumor Microenvironment

thesis
posted on 2024-04-17, 14:18 authored by Sae Rome ChoiSae Rome Choi

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadliest cancer and despite advancements in cancer therapy, remain highly refractory to treatment, largely due to its desmoplastic tumor microenvironment (TME) characterized by complex interactions among cancer cells and stromal components. Particularly, the PDAC associated coagulation system due to leaky tumor vasculatures plays a pivotal role in reshaping the PDAC stroma and its pathogenesis. Understanding the intricate interplay between tumor cells, stromal cells, and the elevated coagulation pathway elements, including tissue factor, thrombin, and fibrin, is essential for developing effective therapeutic strategies. To address these challenges, this research proposes the engineering of a novel PDAC-associated coagulation system using a microfluidic technology, known as coagulation-on-tumor-microenvironment-on-chip (cT-MOC). The study aims to integrate key coagulation pathways in cT-MOC to investigate pivotal interactions in the PDAC stroma: i) thrombin-protease-activated receptors (PARs) mediated promotion of PDAC fibrosis via activation of cancer-fibroblast cross-talk; ii) in-depth analysis of transport and mechanical properties of collagen-fibrin microstructure; iii) inhibited drug delivery in reprogrammed PDAC stroma due to pronounced fibrin deposition on collagen. By leveraging innovative microfluidic technologies and comprehensive experimental approaches, the research endeavors to provide a novel platform that bridges traditional in vitro and in vivo models to overcome the challenges posed by the desmoplastic TME and enhance therapeutic strategies for treatment by targeting the coagulation at the PDAC TME.

History

Degree Type

  • Doctor of Philosophy

Department

  • Mechanical Engineering

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Bumsoo Han

Advisor/Supervisor/Committee co-chair

Jong Hyun Choi

Additional Committee Member 2

Cagri A. Savran

Additional Committee Member 3

Steven T. Wereley

Additional Committee Member 4

Yoon Yeo