Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Ellen Pure

Second Advisor

Margaret Chou

Abstract

Wound healing, chronic fibrosis, and epithelial tumor progression share certain

common hallmarks, including the coagulation cascade, inflammatory response,

activation of mesenchymal stromal cells, and extracellular matrix (ECM) remodeling.

Deregulation of these processes, resulting in chronic inflammation or aberrant

accumulation of ECM components, such as fibrillar collagen or hyaluronic acid (HA),

contributes to exacerbated scar formation and promotes tumorigenesis. Thus, defining

underlying mechanisms governing these processes is vital to understanding disease

progression. CD44 is a transmembrane cell-adhesion receptor that primarily binds to

HA, the predominant glycosaminoglycan found in the ECM. Owing to it ubiquitous

expression on nearly all neuroectodermal-derived cells, CD44 has been implicated in an

array of fibrotic and inflammatory processes. Altered CD44 expression or signaling is

detected in models of acute injury and epithelial tumors, but the role of CD44 in

mediating cellular functionality and matrix remodeling in cutaneous wound healing and

distinct epithelial tumors, such as pancreatic ductal adenocarcinoma (PDA), remains

poorly understood. We demonstrated that in an excisional biopsy punch cutaneous

wound healing model, CD44 mediated the kinetics of fibrotic and inflammatory

responses with ultimate implications in scar formation. During injury resolution, CD44-

null mice exhibited reduced collagen degradation leading to increased fibrillar collagen

accumulation and exacerbated scar formation. These data indicate a previously

unknown role of CD44 in regulating fibrillar collagen accumulation and wound healing in

response to injury. In epithelial tumors, the cross-talk between neoplastic and nonneoplastic

cells is a key determinant of tumor progression. CD44 is expressed in both

neoplastic and non-neoplastic cellular compartments; however, its functionality during

pancreatic tumorigenesis is poorly understood. Using autochthonous tumor models with

tissue-specific CD44 deletion, we found a novel tumor-suppressive role of CD44 on

neoplastic cells, by regulating neoplastic cell proliferation, and tumor-protective role of

CD44 on non-neoplastic cells, by regulating fibrillar collagen accumulation. Together,

these findings demonstrate previously unknown roles of CD44 in mediating underlying

processes that fuel wound healing, fibrosis, and epithelial tumor progression.

Embargoed

Available to all on Tuesday, December 21, 2021

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Included in

Pharmacology Commons

Share

COinS