Mechanisms of Metastasis Suppression and Translational Applications in Thyroid Cancer
Abstract
The incidence of differentiated thyroid cancer (DTC) has risen dramatically over the past several decades. It is currently the 12th most common form of cancer overall and the 5th most common cancer in women. Its increase in incidence is linked to enhanced diagnostic procedures, resulting both in increased diagnosis of early-stage DTC and an increase in the number of individuals who succumb to advanced DTC. Shifts in genomic drivers of DTC during this time indicates that environmental factors may be influencing the biology of DTC, creating more cases and more aggressive disease. Unfortunately, many of the best understood environmental risks for DTC are heightened in military service members. Exposure to ionizing radiation from nuclear accidents and military test sites, and exposure to other environmental factors such as nitrates, low dietary iodine, and dioxins or polycyclic aromatic hydrocarbons may also be associated with DTC. Furthermore, recent data from the gulf war suggest that exposure to burn pit-released airborne dioxins and other chemicals may cause diseases such as cancer, including DTC. Because of its rising incidence, increasing mortality, and unique exposures for military personnel, improving outcomes for soldiers, veterans, and their family members from DTC is the focus of this proposal. Our topic area is thyroid cancer, and our Military Health Focus Area is Environmental Exposure Risk Factors Associated with Cancer, in addition to Mission Readiness. Most patients with DTC are treated using surgery, radioiodine and thyroid stimulating hormone (TSH) suppression. For those who do not respond, the cancers often remains dormant or slowly progressive for decades. However, this stability is often followed by rapid disease progression, during which targeted therapies are employed. Unfortunately, the compounds are not curative, and only improve progression-free survival. In addition, immunotherapies are also not highly effective in DTC. Interestingly, during DTC progression, we only rarely observe new drivers of the disease, such as mutations. This led us to suspect that loss of expression of genes called metastasis progression suppressors (MPS) might be important for DTC progression. We subsequently identified a new MPS gene, RCAN1.4, that when knocked down resulted in increased DTC disease progression and metastasis. We also have recently demonstrated that this knockdown appears to regulate the immune cells of the tumor microenvironment to be more permissive of tumor cell growth, migration, and metastasis. While animal models have been crucial in identifying Regulator of Calcineurin 1.4 (RCAN 1.4) and continue to be important in defining its role, there are aspects of the human immune system that animals fail to accurately recapitulate. In addition to having expertise in thyroid cancer biology, our team has developed a toolbox of bioengineered tools, including tumor organoids and organ-on-a-chip platforms. With these, we have demonstrated the capability to model metastasis of tumor cells from a primary tumor organoid site to downstream target organoid sites using human cells in our metastasis-on-a-chip (MOC) platform. We will deploy this technology to model thyroid cancer using human cancer and immune cells in the proposed studies. Our overall objective will be to define the mechanism for RCAN 1.4 regulation of immune suppression using our novel human cell MOC system to recapitulate the complex biology of DTC and utilize these data to develop biomarkers and potential therapeutic targets to improve outcomes for veterans, wartime fighters, and their family members with DTC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210647
Entities
People
- Matthew D Ringel
Organizations
- Ohio State University
- United States Army