Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering (ENAS)

First Advisor

Levchenko, Andre

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis, due to early metastasis and the limited understanding of the mechanisms driving its progression. In this dissertation, by analyzing bulk transcriptomic profiles from PDAC patients with substantial differences in survival and deconvoluting the results using a single-cell transcriptome dataset of human PDAC, we identified serine protease inhibitor Kazal type 1 (SPINK1) as a crucial modulator of PDAC progression and patient survival. At the patient level, higher SPINK1 expression is correlated with shorter survival, and at the single cell level, SPINK1 expression showed dynamical changes along the trajectory of acinar-ductal metaplasia development trajectories, corresponding to distinct phenotypic states. The subsequent biochemical characterization in PDAC cell lines revealed showed that SPINK1 was a regulator of histone H3 and its modifications, significantly remodeling the chromatin accessibility and promoting the expression of multiple stemness related genes. Furthermore, by utilizing proximity-dependent biotinylation, we discovered a novel signaling axis, where SPINK1 interacts with COL18A1 in the Golgi apparatus, promoting endostatin release and eventually inducing extensive histone H3 modifications. The findings in the effects and mechanism establish a novel link between SPINK1 and epigenomic remodeling in PDAC and also suggest a new therapeutic route to combat PDAC aggressiveness by targeting the SPINK1-COL18A1-endostatin signaling axis.

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