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Recapitulating Immune-driven Stromal Remodeling in Pancreatic Cancer within a Microfluidic Platform
Location: 90
Mentor: Dr. Ashutosh Agarwal
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a five-year survival rate of only 10%. Chemotherapy is the primary treatment, but its effectiveness is hindered by chemoresistance, highlighting the need for tools to study its development and identify new therapeutic approaches. Research indicates that chemoresistance may result from cancer-associated fibroblast (CAF) polarization into an inflammatory state (iCAFs) within the PDAC microenvironment, driven by interactions with myeloid-derived suppressor cells (MDSCs). However, the precise mechanisms and the impact on tumor progression remain unclear. To address these gaps, we developed a microfluidic platform to replicate complex tumor-stromal interactions and monitor MDSC influence in real time. To model PDAC, we engineered dual reporter CAFs to fluoresce green when adopting an inflammatory phenotype and combined them with pancreatic tumor cells to form spheroids. These spheroids interacted with fluidically introduced MDSCs at physiologically relevant levels. Positive and negative polarization controls were established using cytokines TNF-α (pro-inflammatory) and TGF-β (anti-inflammatory). Laminar flow was validated via finite element analysis and particle-imaging velocimetry. Confocal imaging revealed increased CAF polarization in the MDSC and TNF-α groups compared to controls, indicating MDSC involvement in creating an inflammatory microenvironment. Validation will include ELISA assays for IL-6 secretion and RT-qPCR to assess MDSC-induced tumor progression toward a basal phenotype associated with metastasis. Understanding MDSC roles in PDAC progression could reveal novel targets for overcoming chemoresistance.
