Although B-Raf(V600E) is the most common somatic mutation in
papillary thyroid carcinoma (PTC), how it induces
tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-Raf(V600E) gene set signature associated with
tumor progression in PTCs. An independent cohort of B-Raf(V600E)-positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-1 (TSP-1), because it has been previously shown to be important in the regulation of
tumor angiogenesis and
metastasis and is present in abundance in
tumor stroma. Knockdown of B-Raf(V600E) resulted in
TSP-1 down-regulation and a reduction of adhesion and migration/invasion of human
thyroid cancer cells. Knockdown of
TSP-1 resulted in a similar phenotype. B-Raf(V600E) cells in which either B-Raf(V600E) or
TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in
tumor size and fewer pulmonary
metastases from the primary
carcinoma as compared with the control cells. Treatment of orthotopic thyroid
tumors, initiated 1 week after
tumor cell implantation with
PLX4720, an orally available selective inhibitor of B-Raf(V600E), caused a significant
tumor growth delay and decreased distant
metastases, without evidence of toxicity. In conclusion, B-Raf(V600E) plays an important role in PTC progression through genes (i.e., TSP-1) important in
tumor invasion and
metastasis. Testing of a patient's
thyroid cancer for B-Raf(V600E) will yield important information about potential
tumor aggressiveness and also allow for future use of targeted
therapies with selective B-Raf(V600E) inhibitors, such as
PLX4720.