Wen Yu Wong's Abstracts
Wen Yu Wong
Ph.D. Student
Cancer Biology GIDP
Conference Summary
Salivary Gland and Exocrine Biology Gordon Research Conference
Galveston, Texas
Lay Audience Abstract
Worldwide, there are over 560,000 new cases of head and neck cancer each year, with approximately
360,000 deaths. About 90% of these patients receive radiation as their primary treatment and, regrettably, the
surrounding normal salivary glands are collateral damage in 60-80% of these individuals. These patients often
suffer from chronic oral complications such as hyposalivation, mucositis, speech impairments, and malnutrition.
Clinically, there is no definitive cure available to restore salivary functions, and the adverse complications of
radiation often lead to discontinuation of therapy, alterations in treatment schedules, and decreased overall
survival. My project is looking at how the interactions of two proteins, E-cadherin and β-catenin, regulate
chronic loss of salivary functions and, more importantly, what we can do to fix it.
Literature has shown that salivary function and secretion is dependent on E-cadherin and β-catenin
interactions. I have shown that radiation disrupts these two proteins, and this correlates with salivary
dysfunction. My research is designed to study the potential mechanisms by which alterations in E-cadherin and
β-catenin disrupt the salivary secretion wound healing process following radiation treatment and, more
importantly, how it is sustained chronically. If these mechanisms can be elucidated, then small drug molecules
can be discovered that regulate E-cadherin and β-catenin interactions to help restore salivary functions without
further propagating the cancer.
E-cadherin and β-catenin are adhesion molecules – molecules that are necessary for cells to
communicate with each other, stabilize tissue architecture, and allow for transport of essential ion molecules.
Experimental designs have shown that E-cadherin and β-catenin have important roles in embryonic
development and cancer progression. However, their role in preventing tissue regeneration following radiation
treatment is not as well understood. I believe my research will increase the awareness of these two proteins,
their mechanistic regulation, and their potential role in providing more advanced therapeutics following
radiation damage.
One limitation of current models in the field to study salivary regeneration is that they are unable to fully
restore saliva production and function. Our lab has developed a mouse model where injections with insulin
growth factor 1 (IGF1) can fully restore irradiated salivary glands to 100% of total salivary functions found in
untreated mice. Now we have a model that will allow us to investigate how adhesion molecules are altered in
salivary glands following injury and what mechanisms are necessary for restoration.
Regulation of E-cadherin/β-catenin Interactions in Irradiated Salivary Glands
An unintentional side effect of ionizing radiation (IR) treatments for 60-80% of patients with head and neck
cancers is collateral damage to the salivary glands. These patients often suffer from chronic oropharyngeal
complications such as xerostomia, hyposalivation, speech impairments, malnutrition, and a lower quality of life.
Despite recent improvements in palliative care for hyposalivation, compromised wound healing is a challenging
clinical problem that prevents regeneration. Proper wound healing requires the restoration of junctional
contacts to maintain cellular polarity and orientational cues that regulate directional secretion. However,
aberrant polarity could cause compensatory proliferation, a process where apoptotic cells signal to nearby cells
to undergo proliferation. While proliferation is necessary, sustained proliferation in differentiated cells prevents
regeneration. Junctional proteins like E-cadherin, EpCAM, and ZO-1, mediate this repolarization process, by
preventing their transcriptional partners β-catenin, EpICD, and ZONAB from initiating proliferation. To study
this regulation, our lab has developed a mouse model where 5Gy IR treatments to the head and neck region
induce chronic salivary dysfunction. However, mice that receive daily injections of recombinant insulin growth
factor 1 (IGF1) are physiologically capable of restoring salivary functions. We hypothesize that IR-induced
disruption of junctional regulators results in sustained proliferation that prevents salivary regeneration. Using
this model, we have shown that IR induces compensatory proliferation chronically that correlates with salivary
dysfunction. IR induces a decrease in E-cadherin/β-catenin interaction that is sustained chronically at the same
timepoints as compensatory proliferation; and IGF1 can restore this interaction. We have shown that there is
stabilization of β-catenin and an upregulation of β-catenin-regulated proliferative genes like LEF1 and cyclinD1
that could be regulating compensatory proliferation. Additionally, we have preliminary data that suggests
EpCAM might regulate the E-cadherin/β-catenin interaction through preferential binding. Thus, our goal is to
determine how IR-induced disruption of E-cadherin/β-catenin interaction regulates chronic loss of salivary
functions and, more importantly, what we can do to fix it. The long-term goal is to determine the mechanisms
that prevent adult salivary gland