Clinical and therapeutic implications of Sprouty2 feedback dysregulation in BRAF V600E-mutation-positive papillary thyroid cancer

Abstract

Background The BRAF V600E (BRAF+) mutation activates the MAPK/ERK pathway and may confer an aggressive phenotype in papillary thyroid cancer (PTC). However, clinically BRAF+PTC behavior varies from indolent to aggressive. SPRY2 is a negative feedback regulator of the MAPK/ERK pathway. We hypothesize that the level of SPRY2 expression contributes to MAPK/ERK pathway output and accounts for BRAF+ clinical heterogeneity. Methods A tissue microarray with BRAF+PTCs was constructed and analyzed for SPRY2 expression and MAPK/ERK output. Data were studied in the context of clinicopathologic factors to develop a risk stratification system predictive of tumor biology. SPRY2 function was studied by silencing SPRY2 in BRAF+PTC cells. These cells were treated with MAPK/ERK pathway inhibitors and assessed for growth effects. Results BRAF+PTCs with an intact MAPK/ERK feedback pathway, do not exhibit lymph node metastases. BRAF+PTCs with dysregulated feedback pathways have nodal metastasis. When SPRY2 is silenced the BRAF+PTC cells are significantly more sensitive to MAPK/ERK inhibition. Conclusions PTC behavior likely is dependent on both the driver of the MAPK/ERK pathway and its regulatory feedback. When the feedback pathway is intact the tumor phenotype seems to be less aggressive. This has a direct and important clinical implication and may alter our treatment strategies.

The TNM system (version 7) is the most accurate staging system for the prediction of loss of life expectancy in differentiated thyroid cancer

“…In particular, in papillary thyroid cancer, the presence of the BRAF V600E mutation appears to be associated with a markedly worse prognosis, regardless of initial stage, 38 especially in the presence of other molecular cellular abnormalities. 39 In clinical practice, the results of the present study imply that the empirically derived TNM system is a safe choice for any centre that does not wish to go through the extensive and difficult process of deriving and validating a prognostic system for their own patient population. This is in spite of several groups who developed their own prognostic system and who reported that their particular system was superior in their specific patient population.…”

“…Furthermore, in the future, it is not unlikely that current staging systems such as the TNM system, which are based on traditional clinical measures of extent of disease as an indicator for tumour aggressiveness and prognosis, will be superseded by novel or amended with classifications based on molecular markers. In particular, in papillary thyroid cancer, the presence of the BRAF V600E mutation appears to be associated with a markedly worse prognosis, regardless of initial stage, especially in the presence of other molecular cellular abnormalities …”

Mnk1 (Mitogen-Activated Protein Kinase–Interacting Kinase 1) Deficiency Aggravates Cardiac Remodeling in Mice

“…Recent studies have pointed out the significant role of sprouty2, a substrate of Mnk1, during multiple diseases or physiological process such as human mesenchymal stem cell differentiation, 17 papillary thyroid cancer, 18 and prostate cancer progression 19 by regulating ERK signaling pathway. ERK1/2 is one of the most important signaling that could provide new treatment strategies for cardiac hypertrophy and remodeling.…”

Differentiated thyroid cancer—personalized therapies to prevent overtreatment

“…For instance, patients with PTC who have a serine/threonine-protein kinase B-raf (BRAF) Val600Glu mutation differ with regard to the presence of lymph node metastases, depending on the expression level of protein sprouty homologue 2 (SPRY2), a negative regulator of the mitogen-activated protein kinase (MAPK, also known as ERK) pathway; those with a dysregulated MAPK pathway develop lymph node metastases, whereas those with an intact MAPK pathway do not. 38 Once such mechanisms have been identified and individualized therapy adjusted accordingly, it is conceivable that pro cedures such as prophylactic central compartment dissec tion might yield a prognostic advantage. By contrast, there is little discussion about whether surgical removal of lateral neck lymph nodes should only be performed when there is evidence or strong suspicion of the presence of loco regional metastases.…”

“…131 Other cellular pathways and targets, such as protein sprouty homologue 2, need to be dysregulated in addition to the aforementioned mutations in order for a DTC to show a more aggressive clinical behaviour. 38 In this regard, further studies linking molecu lar testing and tumour markers with long-term patient outcomes are needed. The collection of large numbers of tumour samples in tissue banks would facilitate such correlative studies.…”