The TAZ-CAMTA1 Fusion Protein Promotes Tumorigenesis via Connective Tissue Growth Factor and Ras-MAPK Signaling in Epithelioid Hemangioendothelioma.
Clin Cancer Res
; 28(14): 3116-3126, 2022 07 15.
Article
em En
| MEDLINE
| ID: mdl-35443056
ABSTRACT
PURPOSE:
A consistent genetic alteration in vascular cancer epithelioid hemangioendothelioma (EHE) is the t(1;3)(p36;q25) chromosomal translocation, which generates a WWTR1(TAZ)-CAMTA1 (TC) fusion gene. TC is a transcriptional coactivator that drives EHE. Here, we aimed to identify the TC transcriptional targets and signaling mechanisms that underlie EHE tumorigenesis. EXPERIMENTALDESIGN:
We used NIH3T3 cells transformed with TC (NIH3T3/TC) as a model system to uncover TC-dependent oncogenic signaling. These cells proliferated in an anchorage-independent manner in suspension and soft agar. The findings of the cell-based studies were validated in a xenograft model.RESULTS:
We identified connective tissue growth factor (CTGF) as a tumorigenic transcriptional target of TC. We show that CTGF binds to integrin αIIbß3, which is essential for sustaining the anchorage-independent proliferation of transformed NIH3T3/TC cells. NIH3T3/TC cells also have enhanced Ras and MAPK signaling, and the activity of these pathways is reduced upon CTGF knockdown, suggesting that CTGF signaling occurs via the Ras-MAPK cascade. Further, pharmacologic inhibition of MAPK signaling through PD 0325901 and trametinib abrogated TC-driven anchorage-independent growth. Likewise, for tumor growth in vivo, NIH3T3/TC cells require CTGF and MAPK signaling. NIH3T3/TC xenograft growth was profoundly reduced upon CTGF knockdown and after trametinib treatment.CONCLUSIONS:
Collectively, our results demonstrated that CTGF and the Ras-MAPK signaling cascade are essential for TC-mediated tumorigenesis. These studies provided the preclinical rationale for SARC033 (NCI 10015-NCT03148275), a nonrandomized, open-label, phase II study of trametinib in patients with unresectable or metastatic EHE.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Sarcoma
/
Hemangioendotelioma Epitelioide
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article