The Role of Cancer-Associated Fibroblasts in Thyroid Carcinoma

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PROJECT SUMMARY: Thyroid cancer is rapidly increasing in the U.S., with papillary thyroid carcinoma (PTC) as the most common sub- type. While most patients are cured of their thyroid cancer following initial treatment, a significant portion of patients develop aggressive disease. Some PTCs even develop into anaplastic thyroid carcinoma (ATC), a highly lethal and treatment-resistant disease with an abysmal 4-month survival. Cancer-associated fibroblasts (CAFs) have been shown to play an important role in the aggressive behavior and progression of some cancers, including pancreas and triple-negative breast cancer. Preliminary data from our group show that ATCs are defined by a large population of tumor-promoting CAFs that express Fibroblast Activation Protein Alpha (FAP) and Wnt-2 ligand. These CAFs sit along the tumor-stromal interface and likely support a de-differentiated and stem-like phenotype in adjacent tumor cells, as defined by tenascin-C (TNC) expression. We find that small numbers of these FAP+ CAFs are present in a subset of PTCs and serve as a robust biomarker of future disease progression. Our preliminary studies provide compelling evidence that CAF subsets and CAF-derived Wnt ligands drive tumor growth and progression, with elevated levels of Wnt signaling associated with poorly differentiated and aggressive disease. The overall goal of this proposal is to determine the role of CAFs in thyroid malignancy and how their paracrine Wnt signaling supports aggressive tumor behavior. To evaluate the role of CAFs in thyroid cancer, we have collected a cohort of ~300 patients with thyroid disease from Vanderbilt University Medical Center and the University of Washington. We have also created the only thyroid biobank with >50 primary-patient derived thyroid cancer organoids and corresponding CAF cultures. This biobank allows our team to study the thyroid cancer microenvironment across a heterogeneous landscape of morphologies and genetic alterations. Finally, we create a patient-derived xenograft mouse model for thyroid cancer to study the in vivo biology of thyroid cancer and to test new therapeutics (including anti-Wnt drugs) for thyroid cancers resistant to standard-of-care therapy. In this proposal, we will test the hypothesis that distinct CAF subsets (FAP+ Wnt-2+) are present in thyroid cancers and that their secretome drives Wnt- mediated paracrine signaling for tumor progression. In Aim 1, we will define the role of Wnt signaling in thyroid CAF heterogeneity in ATCs, PTCs, and composite tumors showing the transition between both morphologies. In Aim 2, we will define the molecular interaction between Wnt-2 ligand and Tenascin-C (TNC) to promote a stem-like phenotype in ATC. In Aim 3, we will investigate Wnt blockade for stromal reorganization and treatment of ATC. An understanding of the role of CAFs and Wnt signaling will dramatically improve the detection and treatment of the most aggressive forms of thyroid cancer. ATC has limited treatment options and a dismal average survival of ~4 months. Successful completion of these goals will lead directly to clinical trials of novel therapies for ATC that directly target the tumor-promoting stromal microenvironment.