Graduation Date

Spring 5-8-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Surinder K. Batra

Abstract

The mucosal layer that shields the epithelium of the body cavities is made up of high molecular weight, heavily glycosylated proteins called mucins that are broadly categorized into transmembrane and secreted members. Aberrant expression of secreted mucin MUC5AC has been implicated in lung, stomach, and colon cancer pathologies. MUC5AC is expressed de novo in the pancreas upon oncogenic insult, and its abundance in pancreatic tumor and circulation correlates to disease progression. However, few studies have explored beyond the diagnostic and prognostic significance of MUC5AC in pancreatic cancer (PC).

In this dissertation, we sought to investigate the mechanistic contribution of MUC5AC in PC utilizing autochthonous PC murine models (KC: LSL-KrasG12D, Pdx1-Cre; KCM: LSL-KrasG12D, Pdx1-Cre, Muc5ac-/-), human PC cells, and tumor tissues. We demonstrated that MUC5AC promotes PC progression by enriching cancer stem cells via the integrin αvβ5/pSTAT3/KLF4 axis. Further, high MUC5AC expression in PC patients and autochthonous murine tumors facilitated higher resistance to gemcitabine due to the nuclear translocation of β-catenin and subsequent rise in c-Myc-associated glutaminolysis. Co-administration of β-catenin and glutaminolysis inhibitors with gemcitabine abrogated the MUC5AC-mediated chemoresistance in murine and human PC tumoroids. Additionally, KC and KCM tumors revealed significant alterations in the expression of stromal markers, suggesting the contribution of MUC5AC beyond the primary pancreatic tumor. Muc5ac was enriched in the KC adipose tissue (AT), which enhanced the expansion and migration of adipose-derived mesenchymal stem cells (AD-MSCs) via the CXCR2 and Rac1 axis, respectively. Mass spectrometry analyses revealed that Muc5ac scaffolds CXCR2 ligands in AT and serum of tumor-bearing mice and PC patients, thereby acting as a carrier of tumor secretome to distant sites. Muc5ac-mediated AD-MSC mobilization led to increased α-SMA+ cancer-associated fibroblasts (CAFs) in the Muc5ac-expressing pancreatic tumors.

Owing to the dense tumor stroma and therapy-refractory nature, PC patients demonstrate a dismal survival rate. Hence, evaluating the mechanistic implications of secreted molecule MUC5AC in regulating local and systemic events in the PC landscape may bolster prognostication and therapeutic strategies to improve clinical outcomes.

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