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PAX3-FOXO1 is essential for tumor initiation and maintenance but not recurrence in a human myoblast model of rhabdomyosarcoma

Wednesday, September 14, 2016 — Poster Session I

3:00 p.m. – 4:30 p.m.
FAES Terrace
NCI
CANCER-15

Authors

  • PR Pandey
  • B Chatterjee
  • J Khan
  • MM Miettinen
  • SM Hewitt
  • FG Barr

Abstract

The PAX3-FOXO1 fusion gene is generated by a 2;13 chromosomal translocation, and is a characteristic feature of an aggressive subset of rhabdomyosarcoma (RMS). To dissect the mechanism of oncogene action during RMS tumorigenesis and progression, doxycycline-inducible PAX3-FOXO1 and constitutive MYCN expression constructs were introduced into immortalized human myoblasts. Though myoblasts expressing PAX3-FOXO1 or MYCN alone were not transformed in focus formation assays, combined PAX3-FOXO1 and MYCN expression resulted in transformation. Following intramuscular injection into immunodeficient mice, myoblasts expressing PAX3-FOXO1 and MYCN formed rapidly growing RMS tumors whereas myoblasts expressing only PAX3-FOXO1 formed tumors after a longer latency period. Doxycycline withdrawal following tumor formation in vivo or focus formation in vitro resulted in tumor regression or smaller foci associated with myogenic differentiation and cell death. Following regression, most tumors recurred in the absence of doxycycline. Analysis of recurrent tumors revealed a subset without PAX3-FOXO1 expression, and cell lines derived from these recurrent tumors demonstrated transformation in the absence of doxycycline. Cell lines derived from primary tumors were dependent on PAX3-FOXO1 and differentiated following doxycycline withdrawal but recurrent tumor-derived cells without PAX3-FOXO1 expression did not differentiate under these conditions. These findings indicate that PAX3-FOXO1 collaborates with MYCN during early RMS tumorigenesis to dysregulate proliferation and inhibit myogenic differentiation and cell death. Although most cells in the primary tumors are dependent on PAX3-FOXO1, recurrent tumors can develop by a PAX3-FOXO1-independent mechanism, in which rare cells are postulated to acquire secondary transforming events that were activated or selected by initial in vivo PAX3-FOXO1 expression.

Category: Cancer Biology