Cancer-Associated Fibroblasts Positively Correlate with Dedifferentiation and Aggressiveness of Thyroid Cancer

Shishuai Wen,1,2,* Ning Qu,1,2,* Ben Ma,1,2,* Xiao Wang,1,2,* Yi Luo,1,2,* Weibo Xu,1,2 Hongyi Jiang,1,2 Yan Zhang,2,3 Yu Wang,1,2 Qinghai Ji1,2 1Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinghai Ji; Yu WangDepartment of Head & Neck Surgery, Fudan University Shanghai Cancer Center, No. 270, Dong’an Road, Shanghai, 200032, People’s Republic of ChinaFax +021 6404 0207Email jq_hai@126.com; neck130@sina.comBackground and Objectives: Targeting cancer-associated fibroblast (CAF) is being explored as an approach to improve cancer therapies. The roles of CAF remain unclarified in malignant transformation of papillary thyroid cancer (PTC) into dedifferentiated thyroid cancer (DDTC). This study aimed to investigate correlations of CAF with dedifferentiation and clinicopathological characteristics of thyroid cancer.Materials and Methods: We applied three different mRNA-based CAF gene signatures to quantify CAF in our cohort, the Gene Expression Omnibus (GEO) cohort and The Cancer Genome Atlas (TCGA) cohort, and analyzed expression of α-SMA by immunohistochemistry in thyroid cancer. The CAF score was analyzed for its associations with clinicopathological characteristics, genetic mutations, tumor-associated signaling pathways and immune landscape.Results: The CAF score increased significantly in DDTCs compared with normal thyroid tissues and PTCs, and the α-SMA-positive CAFs were found enriched in DDTCs. The high CAF score showed a significant correlation with the anaplastic phenotype in DDTC and low thyroid differentiation score in PTC. Patients with a high CAF score remarkably increased the risk of aggressive outcomes in both DDTC and PTC. Furthermore, the CAF score was positively correlated with genetic mutations, oncogenic signaling pathways, the immune score and increased expression of tumor microenvironment (TME) target markers.Conclusion: Our findings suggest CAFs positively correlate with dedifferentiation and aggressive outcomes of thyroid cancer, and targeting CAFs as a therapeutic approach may benefit DDTC patients.Keywords: CAF, dedifferentiation, DDTC, PTC