Graduation Date

Fall 12-19-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Surinder K. Batra

Second Advisor

Sushil Kumar

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal malignancies, in part due to its dense fibrotic stroma and immunosuppressive microenvironment. This dissertation identified cancer-associated mucins (oncoMUCs), particularly MUC4 and MUC16, as central coordinators of these phenotypes. Multiplex imaging and transcriptomic profiling revealed stage-specific clonal diversity in oncoMUC expression, with elevated MUC4 and MUC16 modulating a signaling network that regulates multiple immune checkpoints. Functional studies in murine models demonstrated that oncoMUCs converge on EGFR and UNC5B pathways to drive TIM3, VISTA, and PD-L1 expression, reinforcing immune evasion.

Therapeutically, co-inhibition of oncoMUC signaling and mutant KRAS using Istradefylline and MRTX1133 significantly reduced tumor burden, suppressed checkpoint expression, and restored CD8+ T-cell function, suggesting a promising combinatorial strategy. Beyond immune modulation, this work revealed a novel role for MUC16 in extracellular matrix (ECM) remodeling. In contrast to prior assumptions that collagen is primarily stromal-derived, we showed that PDA cells produce and organize key collagen isoforms, notably Col4a2, in response to complement signaling.

MUC16-expressing cancer cells activate the complement cascade via factor D, triggering ERK and NFκB pathways in both cancer cells and fibroblasts. This promotes a fibrotic ECM and supports survival under detachment stress, aiding metastasis. Col4a2,

retained at the cancer cell surface, may function not only structurally, but also as a survival ligand via integrin-AKT signaling. Together, these findings positioned oncoMUCs as drivers of immune suppression, ECM reprogramming, and metastatic fitness.

By redefining the roles of mucins and complement in PDA, this work highlighted the tumor-intrinsic mechanisms that reshape the stroma to favor dissemination. It also established a framework for mucin-directed therapeutic strategies that address both epithelial and microenvironmental barriers to effective treatment.

Comments

2025 Copyright, the authors

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Available for download on Friday, December 10, 2027

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