A bioengineering approach to investigating the possible role of fibronectin in neuroblastoma dormancy and relapse

Abstract

ABSTRACT : Neuroblastoma (NB) is the most common extracranial solid tumor in children and is frequently diagnosed at a metastatic stage. Despite therapy, tumor relapse occurs for around 50% of high-risk NB patients. At relapse, these patients have a very poor prognosis and overall survival rate decreases. The mechanisms behind NB relapse are not well understood, but recent studies suggest that chemoresistant dormant cells are in part responsible for tumor recurrence. Fibronectin (Fn) is an extracellular matrix protein (ECM) shown to promote breast cancer cell dormancy in a TGFβ1-dependent manner. Fn presents three regions of alternative splicing: extra domain A (EDA), extra domain B (EDB), and type III constant segment (IIICS). The presence of EDA-containing Fn (EDA+ Fn) in the ECM generates a positive feedback loop by activating the TGFβ1 signaling pathway, which in turn promotes the expression of EDA+ Fn. Besides its role in dormancy, the activation of the TGFβ1 signaling pathway promotes the differentiation of stromal fibroblasts towards cancer-associated fibroblasts (CAFs), which are known to promote tumor progression and chemoresistance. Altogether, we hypothesized that the ECM protein fibronectin, and specifically EDA+ Fn, could play a critical role in neuroblastoma dormancy, chemoresistance, and relapse by activating the ERK signaling pathway in NB cells and the TGFβ1 signaling pathway in fibroblasts of the tumor environment. To validate our hypothesis here we propose three specific aims; (i) to demonstrate that fibronectin induces cancer cell dormancy and relapse in neuroblastoma; (ii) to elucidate the role of the EDA domain in Fninduced dormancy and relapse; (iii) to demonstrate how EDA+ Fn plays a crucial role in CAF activation, initiating an ECM-remodeling process that promotes tumor growth and progression.