Graduation Date

Summer 8-15-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Prakash Radhakrishnan

Second Advisor

Michael A Hollingsworth

Abstract

Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers and is extremely lethal. Late-stage presentation increases the need for standard-of-care regimens including gemcitabine/Abraxane or FOLFIRINOX, which have negligible benefit, as evidenced by the five-year overall survival rate of an abysmal 13%. Driver mutations in the KRAS oncogene are a defining feature of this malignancy. KRAS acts, at least in part, by increasing the expression of a cell-surface glycoprotein called Mucin-16 or MUC16. MUC16 (absent in the normal pancreas) is expressed in >65% of PDAC cases and associated with poor survival. MUC16-expressing tumor cells have higher activation of ErbB-1/2/3, PI3K/AKT, MAPK, and NF-κB pathways that promote cancer progression. Chapter 2 of this dissertation focuses on using MUC16 as a tumor-specific biomarker for diagnostic imaging. We show the design and synthesis of a MUC16 -binding antibody-based MRI probe conjugated to a gadolinium-based contrast agent that facilitates the detection of early- and late-stage PDAC lesions in preclinical mouse models. In Chapter 3, we demonstrate that the aberrant glycoforms of MUC16 exacerbate aggressive behavior in PDAC cells and mediate signaling through a4b1 integrins and downstream integrin-linked kinase (ILK) and focal adhesion kinase (FAK) to increase the migratory properties of PDAC cells, fueling metastatic progression. Targeting MUC16 using the antibody AR9.6 perturbs such oncogenic signaling/migration. In Chapter 4, we uncover a novel role for MUC16 in mediating immunosuppression. The PDAC tumor microenvironment has immunosuppressive cells, of which macrophages form the bulk. We demonstrate that loss of MUC16 causes diminished tumor burden. MUC16KO tumors have low numbers of M2-like CD206+ or Ym1/2+ macrophages, compared to the MUC16-competent tumors. We identify CCL2 and Serpin-E1 as mediators of macrophage infiltration. Lastly, we show that sustained clodronate liposome administration facilitates macrophage depletion in the spleen, and influences tumor burden – specifically lowering tumor burden in KPC (MUC16-expressing) tumors. However, splenic regulatory T cell appearance is a possible mechanism of resistance to long-term myeloid depletion. Hence, we discuss the utility of immune reprogramming strategies like CD40 agonists in combination with anti-MUC16 strategies to facilitate long-term tumor regression.

Comments

2025 Copyright, the authors

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