Identification of R-Spondin Gene Signature Predictive of Metastatic Progression in BRAFV<sup>600E</sup>-Positive Papillary Thyroid Cancer
Sabrina Daniela da Silva,
Grégoire B. Morand,
Luciana Diesel,
Jefferson Muniz de Lima,
Krikor Bijian,
Senthilkumar Kailasam,
Francois Lefebvre,
Guillaume Bourque,
Michael Hier,
Moulay A. Alaoui-Jamali
Affiliations
Sabrina Daniela da Silva
Department of Otolaryngology—Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
Grégoire B. Morand
Department of Otolaryngology—Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
Luciana Diesel
Department of Otolaryngology—Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
Jefferson Muniz de Lima
Department of Otolaryngology—Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
Krikor Bijian
Lady Davis Institute for Medical Research/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
Senthilkumar Kailasam
Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada
Francois Lefebvre
Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada
Guillaume Bourque
Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada
Michael Hier
Department of Otolaryngology—Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
Moulay A. Alaoui-Jamali
Lady Davis Institute for Medical Research/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland and early stages are curable. However, a subset of PTCs shows an unusually aggressive phenotype with extensive lymph node metastasis and higher incidence of locoregional recurrence. In this study, we investigated a large cohort of PTC cases with an unusual aggressive phenotype using a high-throughput RNA sequencing (RNA-Seq) to identify differentially regulated genes associated with metastatic PTC. All metastatic PTC with mutated BRAF (V600E) but not BRAF wild-type expressed an up-regulation of R-Spondin Protein 4 (RSPO4) concomitant with an upregulation of genes involved in focal adhesion and cell-extracellular matrix signaling. Further immunohistochemistry validation confirmed the upregulation of these target genes in metastatic PTC cases. Preclinical studies using established PTC cell lines support that RSPO4 overexpression is associated with BRAF V600E mutation and is a critical upstream event that promote activation of kinases of focal adhesion signaling known to drive cancer cell locomotion and invasion. This finding opens up the potential of co-targeting B-Raf, RSPO and focal adhesion proteins as a pharmacological approach for aggressive BRAF V600E PTC.
