Atypical localization of Eph-RTKs in childhood cancer rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS), the most common soft tissue tumor in children, is an aggressive cancer with a 5-year survival rate of 24% if it has metastasized. Current treatment options are limited to surgery, chemotherapy and radiation, so there is a significant unmet need for targeted therapies. Eph receptor tyrosine kinases have been implicated in the development and progression of many other tumor types. Recent results from our group identified several Eph receptors expressed by primary muscle stem cells (satellite cells), which led us to screen for protein expression of Ephs in canine RMS primary tumors as well as mouse and human RMS cell lines. Intriguingly, we noted strong expression but abnormal localization of one Eph receptor: in multiple tumors from all three species, we detected EphA1 in the nucleus of interphase cells. Mislocalization of RTKs to the nucleus in other tumor types has been shown to promote cancer progression, with the classic case being ErbBs. There are only two published studies about Ephs localizing to the nucleus and to date no other nuclear RTKs have been identified in RMS. These data represent the first case of a nuclear RTK in RMS, and the first time that EphA1 has been detected in the nucleus of any cell type.