Age-related changes to the senescence associated secretory phenotype of thyroid tissue in papillary thyroid carcinoma

Project Summary & Abstract Advanced age is associated with compromised outcomes in differentiated thyroid cancer. This observation suggests that there is a biologic change due to aging that causes the poorer prognosis for the older adult. Studies of the aging thyroid have reported that detrimental immune modulation and cellular senescence contribute to thyroid diseases in the older adult, both of which have been implicated in the progression of malignancies. Aging is associated with a state of chronic inflammation due to the secretion of inflammatory proteins collectively known as the senescence-associated secretory phenotype (SASP) from senescent cells. There is a critical need to understand the connection between immune modulation and cellular senescence via the SASP and tumor progression in older adult patients. Our long-term goal is to better characterize the role of age-associated immune modulation in the development and progression of papillary thyroid carcinoma (PTC) in the older adult population. The overall objective of this proposed study is to elucidate the interplay of age and SASP production in thyroid tissue to guide personalized management of older adult patients with PTC. Our central hypothesis is that advanced age induces an SASP transcriptome in senescent thyroid fibroblasts that leads to enhanced progression of PTC. This hypothesis will be tested using publicly available large RNA sequencing datasets and single-cell RNA sequencing technology to pursue two specific aims: (1) to identify the contribution of advanced age to the SASP in thyroid tissue and (2) to identify alterations in the SASP transcriptome of aged thyroid fibroblasts due to local and locoregionally advanced PTC. This project is innovative because it is the first study to characterize the contribution of age to SASP production in normal thyroid tissue and leverage deconvolution techniques to isolate senescent thyroid fibroblasts of older adults to examine how the SASP contributes to PTC progression. The proposed research will establish validity for the unique SASP transcriptome in thyroid tissue and thyroid disease and lay the groundwork for further mechanistic studies into the role of older adult immune modulation in thyroid diseases.