Abstract 1525: Upregulation of genes linked to epithelial-mesenchymal transition in anaplastic thyroid cancer

Abstract

Introduction: Epithelial-mesenchymal transition (EMT) plays a major role in invasion, migration, and drug resistance in cancer. There are several signaling pathways associated with EMT, including PI3K/Akt and NFΚB. EMT is present in several cancer types, especially in the recurrent and metastatic setting. Anaplastic thyroid cancer (ATC) accounts for 2% of thyroid cancers and are notoriously aggressive. Clinically, these patients have poor survival rates and are resistant to standard of care therapies. ATC can arise de novo from follicular thyroid cells or in association with papillary thyroid carcinoma (PTC). Therefore, we investigated the differences in gene signature and cancer pathway expression in these histological subtypes, and their potential association with genes upregulated in EMT. Methods: De novo ATC and mixed ATC/PTC cases (N=12) from 1998 to 2018 with viable formalin-fixed paraffin-embedded (FFPE) tissue were identified and selected. 8 cases exhibited both PTC and ATC components while the rest (N=4) were pure ATC cases, as confirmed by a pathologist. In the 4 mixed ATC/PTC histology group specimen, 3 were identified by a pathologist to contain greater than 80% ATC involvement while the fourth was characterized as 40% ATC and 60% PTC. The NanoString PanCancer Pathway panel, which contains 770 genes from 13 signaling pathways, was performed with the extracted tumor RNA to evaluate and compare the gene signatures of the pure ATC versus mixed ATC/PTC cases. Results: Majority of patients (N=11, 92%) developed metastatic disease, a common feature of ATC, and are currently deceased (N=10, 83%). Using Nanostring panel on the patient specimen, we identified differential expression of genes and cancer pathways in the mixed ATC/PTC cohort in comparison to the pure ATC cohort. 28 genes, strongly associated with cancer pathways including MAPK, cell cycle-apoptosis, driver genes, and RAS, were significantly upregulated with at least two-fold change in the mixed ATC/PTC histology group in comparison to the pure ATC histology group (p<0.01). Three genes strongly linked with EMT demonstrated increased expression. MMP3 was the most upregulated gene in the mixed ATC/PTC histology group, with a 41.4 linear fold change (p=0.001), and has been shown to induce EMT in various cancers. Two other EMT-related genes, TNF and PIK3CG, were similarly significantly expressed in the mixed ATC/PTC versus the pure ATC histology group (p<0.005). Conclusion: Our results demonstrate a significant difference in the expression of cancer-related genes between the mixed ATC/PTC and the pure ATC histology groups. Our findings also suggest a correlation between mixed ATC/PTC histology cases and genes associated with EMT. Citation Format: Rebecca R. Pharaon, Hannah J. Young, Kimberley-Jane C. Bonjoc, Feras Ally, Holly Yin, Robert Kang, Thomas Gernon, Ammar Chaudhry, Ellie Maghami. Upregulation of genes linked to epithelial-mesenchymal transition in anaplastic thyroid cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1525.

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

“…Morphologically, ATC is composed by undifferentiated cells that even if retaining some features indicatives of their epithelial origin have largely acquired a mesenchymal phenotype [ 2 ]. The current hypothesis is that ATCs rarely develop as ex-novo lesions, but rather evolve from pre-existing well-Differentiated Thyroid Carcinoma (DTC) through a process of trans-differentiation that likely relies on the Epithelial-to-Mesenchymal Transition (EMT) process [ 3 – 5 ].…”