Abstract 3134: Hierarchical gene master regulators of papillary and anaplastic thyroid cancer phenotype

Abstract

Abstract The incidence of thyroid cancer (TCa) has doubled in the last decade. Papillary thyroid cancer (PTC), that comprises of 80% of all TCas, is treatable with great outcomes. However, undifferentiated anaplastic thyroid cancer (ATC), with very poor prognosis, is considered a clinical challenge and currently a losing battle. Moreover, the molecular mechanisms responsible for various forms of TCa are largely unknown. We believe that the cells of histopathologically distinct regions of a heterogeneous thyroid tumor are governed by different sets of master gene regulators. The smart manipulation of such master genes will be able to selectively destroy cancer cells but not normal tissue, opening a novel and much more effective avenue in the thyroid cancer targeted gene therapy. Our analysis established the gene hierarchical governance in each region based on their Gene Commanding Height (GCH). GCH is a measure that combines the gene expression coordination with other genes and the expression stability among biological replicas provided by the internal homeostatic mechanisms. Here, we provide experimental evidence that standard papillary (BCPAP) and anaplastic (8505C) human thyroid cancer cell lines have different master regulators. We identified the master regulators of BCPAP and 8505C, and determined their GCH. Transfection of master gene regulators of a particular cell line has significantly larger effects on the cell line they command than on other cells. We found that the stable transfection with TMEM194A, a nuclear envelope protein, regulated twice more genes in BCPAP than in 8505C cells. The analysis using human thyroid cancer cells reaffirmed our hypothesis of the existence of hierarchical master gene regulators and that the phenotypic changes can be manipulated with the introduction of these genes. We further validate these concepts using human thyroid biopsy samples. We found substantial differences in the GCH scores of cancer versus normal tissue of a surgically removed 32.0mm papillary carcinoma from the left lobe of a 33y old male. Because of such differences between the cancer region and the normal tissue, manipulation of cancer regulators is expected to affect the cancer cells in a greater degree than the normal cells. These results suggest that we have defined a master gene regulator hierarchy in thyroid cancer and extrapolation of this analysis to compare anaplastic and papillary thyroid cancer will lead to novel gene therapeutic modalities. Our long-term goal is to identify master regulators of cancer nodules for each patient and develop personalized cancer therapy targeting these master regulators. Citation Format: Neha Yashpal Tuli, Craig Berzofsky, Rachana Maniyar, Sanjukta Chakraborty, Ghada Ben Rahoma, Sarnath Singh, Jan Geliebter, Raj K. Tiwari, Sanda Iacobas, Dumitru A. Iacobas. Hierarchical gene master regulators of papillary and anaplastic thyroid cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3134. doi:10.1158/1538-7445.AM2017-3134