The TAZ-CAMTA1 Fusion Protein Promotes Tumorigenesis via Connective Tissue Growth Factor and Ras–MAPK Signaling in Epithelioid Hemangioendothelioma

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 co-activator that drives EHE. Here, we aimed to identify the TC transcriptional targets and signaling mechanisms that underlie EHE tumorigenesis. Experimental Design: 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 αIIbβ3,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, pharmacological 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 non-randomized, open-label, phase 2 study of trametinib in patients with unresectable or metastatic EHE.

H. pylori‐induced NF‐κB‐PIEZO1‐YAP1‐CTGF axis drives gastric cancer progression and cancer‐associated fibroblast‐mediated tumour microenvironment remodelling

“…CTGF's pivotal role in spearheading fibrotic diseases and its involvement in various cancers has been well‐documented 50 . Elevated CTGF levels within CAFs have been associated with a reduced disease‐free survival rate in patients 51–54 . Remarkably, our co‐staining experiments involving α‐SMA, PIEZO1 and YAP1 unveiled a positive interrelation among these markers in H. pylori + GC patients (Figure 5A,B).…”

“…50 Elevated CTGF levels within CAFs have been associated with a reduced disease-free survival rate in patients. [51][52][53][54] Remarkably, our co-staining experiments involving α-SMA, PIEZO1 and YAP1 unveiled a positive interrelation among these markers in H. pylori + GC patients (Figure 5A,B). This observation was further substantiated by the TCGA GC database, which highlighted a positive correlation between YAP1-CTGF, PIEZO1 and CAF biomarkers (Figure 5C,D).…”

The oncogenic fusion protein TAZ-CAMTA1 promotes genomic instability and senescence through hypertranscription

“…However, this also leaves TC-expressing endothelial cells susceptible to acquiring a growth-promoting secondary mutation. Previous studies have highlighted TC expression as being the initiating event in EHE development, however have used either contextually non-relevant cell lines or mouse models which take a long time to generate tumours 5,9,[12][13][14]39 . Using our model system, we provide a mechanistic explanation for previously unanswered questions about the unique clinical features of EHE within a contextually relevant, in vitro model.…”

Epithelioid hemangioendothelioma (EHE) with WWTR1::TFE3 gene fusion, a novel fusion variant

“…Studies on EHE have confirmed that both WWTR1::CAMTA1 and YAP1::TFE3 alone are capable of driving EHE oncogenesis. 3,10,11 Based on the domain rearrangements seen in WWTR1::CAMTA1 and YAP1::TFE3 fusions, we hypothesized that the WWTR1::TFE3 fusion oncoprotein would exhibit tumorigenic activity.…”