TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition

Masumi Tsuda, Ian J. Davis, Pedram Argani, Neerav Shukla, Gael G. McGill, Makoto Nagai, Tsuyoshi Saito, Marick Laé, David E. Fisher, Marc Ladanyi

Research output: Contribution to journalArticle

Abstract

Specific chromosomal translocations encoding chimeric transcription factors are considered to play crucial oncogenic roles in a variety of human cancers but the fusion proteins themselves seldom represent suitable therapeutic targets. Oncogenic TFE3 fusion proteins define a subset of pediatric renal adenocarcinomas and one fusion (ASPL-TFE3) is also characteristic of alveolar soft part sarcoma (ASPS). By expression profiling, we identified the MET receptor tyrosine kinase gene as significantly overexpressed in ASPS relative to four other types of primitive sarcomas. We therefore examined MET as a direct transcriptional target of ASPL-TFE3. ASPL-TFE3 binds to the MET promoter and strongly activates it. Likewise, PSF-TFE3 and NONO-TFE3 also bind this promoter. Induction of MET by ASPL-TFE3 results in strong MET autophosphorylation and activation of downstream signaling in the presence of hepatocyte growth factor (HGF). In cancer cell lines containing endogenous TFE3 fusion proteins, inhibiting MET by RNA interference or by the inhibitor PHA665752 abolishes HGF-dependent MET activation, causing decreased cell growth and loss of HGF-dependent phenotypes. MET is thus a potential therapeutic target in these cancers. Aberrant transcriptional up-regulation of MET by oncogenic TFE3 fusion proteins represents another mechanism by which certain cancers become dependent on MET signaling. The identification of kinase signaling pathways transcriptionally up-regulated by oncogenic fusion proteins may reveal more accessible therapeutic targets in this class of human cancers.

Original languageEnglish (US)
Pages (from-to)919-929
Number of pages11
JournalCancer Research
Volume67
Issue number3
DOIs
StatePublished - Feb 1 2007

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Up-Regulation
Hepatocyte Growth Factor
Alveolar Soft Part Sarcoma
Neoplasms
Proteins
Proto-Oncogene Proteins c-met
Therapeutics
Genetic Translocation
RNA Interference
Renal Cell Carcinoma
Sarcoma
Transcription Factors
Phosphotransferases
Pediatrics
Phenotype
Cell Line
Growth
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. / Tsuda, Masumi; Davis, Ian J.; Argani, Pedram; Shukla, Neerav; McGill, Gael G.; Nagai, Makoto; Saito, Tsuyoshi; Laé, Marick; Fisher, David E.; Ladanyi, Marc.

In: Cancer Research, Vol. 67, No. 3, 01.02.2007, p. 919-929.

Research output: Contribution to journalArticle

Tsuda, Masumi ; Davis, Ian J. ; Argani, Pedram ; Shukla, Neerav ; McGill, Gael G. ; Nagai, Makoto ; Saito, Tsuyoshi ; Laé, Marick ; Fisher, David E. ; Ladanyi, Marc. / TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. In: Cancer Research. 2007 ; Vol. 67, No. 3. pp. 919-929.
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