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.
Recommended Citation
Govindaraju, Priya Krishna, "Cd44-Mediated Collagen Remodeling Drives Wound Resolution And Pancreatic Tumorigenesis" (2018). Publicly Accessible Penn Dissertations. 3119.
https://repository.upenn.edu/edissertations/3119