Graduation Date

Spring 5-9-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Moorthy Palanimuthu Ponnusamy

Abstract

Pancreatic cancer (PC) is among the most lethal solid malignancies, characterized by rapid progression, early metastasis, profound therapeutic resistance, and frequent recurrence. Increasing evidence identifies pancreatic cancer stem cells (PCSCs) as critical drivers of these aggressive phenotypes. PCSCs exhibit self-renewal capacity, phenotypic plasticity, and enhanced survival mechanisms that sustain tumor propagation and enable relapse following therapy. Notably, cancer stem cells share conserved transcriptional and functional programs with normal embryonic and adult progenitor stem cells. However, the early pluripotency-associated factors reactivated during oncogenic transformation, and their mechanistic contributions to pancreatic cancer stemness, remain poorly defined.

This dissertation investigates the molecular regulation of pancreatic cancer stemness with a particular focus on neurotransmitter-mediated signaling. We identified SLC22A3 as a stemness maintenance marker through comparative analysis of stemness-associated transcriptomes from embryonic stem cells (ESCs), pancreatic cancer (PC), and normal pancreatic tissues. Through integrated molecular, cellular, and functional analyses, we identify the organic cation transporter SLC22A3 (OCT3) as a previously unrecognized embryonic stem cell–associated signature that is reactivated in pancreatic cancer stem cells. SLC22A3 expression is significantly enriched in CSC populations compared to non-stem tumor cells, suggesting a selective role in maintaining stem-like states. Loss-of-function studies demonstrate that genetic knockdown of SLC22A3 in pancreatic cancer models results in a marked reduction of core stemness markers, including transcription factors associated with self-renewal and pluripotency, thereby impairing CSC maintenance. Mechanistically, this work establishes a link between SLC22A3 and serotonin (5-hydroxytryptamine, 5-HT) signaling in pancreatic cancer. SLC22A3 transports serotonin in pancreatic cancer cells, and serotonin treatment enhances the expression of stemness-associated genes, supporting a model in which SLC22A3-mediated serotonin uptake promotes the maintenance of CSC phenotypes. Additionally, serotonin mediates stemness via downstream histone modifications, particularly histone serotonylation, enhancing the expression of stemness-associated genes. By identifying SLC22A3 as a key regulator of serotonin-mediated CSC maintenance, this work reveals a previously unexplored vulnerability in pancreatic cancer and supports the therapeutic targeting of cancer stem cell dependencies as a strategy to overcome resistance and improve long-term treatment outcomes. Furthermore, Verteporfin, an FDA-approved drug, has been repurposed as an effective agent that sensitizes tumors to chemotherapy by targeting CSC populations.

Collectively, this dissertation uncovers a novel neuro-metabolic axis governing pancreatic cancer stemness and provides mechanistic insight into how embryonic-like programs are reactivated during tumor progression. Latter findings also highlight the potential of repurposing clinically approved drugs to overcome resistance mechanisms.

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