Abstract 3781: MYCN-induced TRPM7 mediates calcium influx and promotes neuroblastoma cell migration.

Abstract

Abstract Neuroblastoma (NB) is the most common extra-cranial solid cancer in children. One of the genetic characteristics of advanced stage NB is MYCN gene amplification, a prognostic indicator of poor outcome. MYCN is a transcription factor from the myc proto-oncogene family that regulates fundamental processes by regulating the expression of genes that are involved in cell proliferation, growth, cell migration, etc. One of the hallmarks of the malignant progression of primary tumors is uncontrolled growth and spread of tumor cells, with the consequence of metastatic cells entering the blood stream or lymphatic system and nesting into secondary tissues and organs. Metastatic tumors affect the function of cells and/or organs at the secondary site, and compromise the health and survival of cancer patients. Recent studies have shown that the multiple steps involved in cell migration and invasion (such as lamellapodia formation, focal adhesion turnover, and cytoskeletal dynamics) are dependent on the availability of free intracellular calcium. Although significant advances have been made in understanding the role of calcium during migration and invasion itself, little has been achieved towards understanding its impact on the progression of diseases such as cancer where cell motility is critical for the spread of tumor cells. To address this deficiency, the objective of the current study was to elucidate the mechanism by which calcium signaling regulates NB migration and invasion. Our initial results showed that tetracycline-inducible over-expression of MYCN in NB cells increased TRPM7 expression, enhanced calcium signaling, and promoted cell migration, compared to control NB cells. In addition, increasing extracellular calcium augmented these processes. These results implicate TRPM7 as a potential regulator of calcium-dependent NB cell migration and invasion. In order to confirm the role of TRPM7 in these processes, we used pharmacological inhibitors of TRPM7 and TRPM7-specific siRNA to modulate TRPM7 activity in NB cells, and performed live-cell calcium measurements, electrophysiological patch-clamp recordings, and cell migration assays. The results showed that TRPM7 plays a role in regulating intracellular calcium signaling and NB cell migration. Overall, the results from this study suggest that MYCN over-expression and minute changes in extracellular calcium can promote NB cell migration and invasion through a process that involves TRPM7. Furthermore, this study identifies a new biomarker for NB (TRPM7) and novel target for the development of more effective chemotherapeutic drugs for the treatment of advanced stage NB. Citation Format: Ingo Lange, Dana-Lynn T. Koomoa. MYCN-induced TRPM7 mediates calcium influx and promotes neuroblastoma cell migration. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3781. doi:10.1158/1538-7445.AM2013-3781