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

Abstract

TAZ-CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ-CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ-CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ-CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ-CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ-CAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.

Current Model Systems for Investigating Epithelioid Haemangioendothelioma

“…Here, RNA-sequencing confirmed that TC or YT mediates a transcriptional programme similar, but not identical, to the activated TAZ/YAP mutants TAZ4SA and YAP5SA [10]. This is in agreement with transcriptomic studies using alternative EHE model systems [11,38,39,[61][62][63].…”

“…In recent years, a range of model systems for investigating EHE have been reported, and together have greatly improved our understanding of the disease [10,38,39,[60][61][62][63]. These include in vitro and in vivo systems established using different approaches (Table 1).…”

“…Attempts to express the TC fusion protein in primary endothelial cells, such as human umbilical vein endothelial cells (HUVECs), have been unsuccessful. Our work has addressed this issue by developing an EHE model whereby endothelial cells are derived from mouse embryonic stem cells (mESCs), an approach used successfully to study various other diseases [63,71,72] (Figure 2). The differentiation protocol entailed the generation of embryoid bodies (EBs) from mESCs, from which an endothelial progenitor population was isolated and re-plated for further culture [63].…”

Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

“…Their dysregulation or inhibition can wreak havoc, influencing a plethora of crucial pathways and mechanisms. These include DNA damage triggered by hypertranscription or via ATM-P53 axis, arrest in G1 and S-phase of the cell cycle, HR and NHEJ defects due to the suppression of BRCA1-RAD51 and HDAC1 activation, instigating T-cell acute lymphoblastic leukemia by modifying the NOTCH1, PTEN-PI3K-AKT, and MYC pathways, curtailing platelet function by impacting cyclic nucleotide pathways, undermining hemostasis by inhibiting platelet clumping through the reduction in αIIbβ3 expression, obstructing DNA replication due to changes in the RBBP6/ZBTB38/MCM10 axis, and imbalancing the proliferation-to-apoptosis ratio of lymphocytes, among others [9,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29].…”

“…Interestingly, a significant portion of the genes implicated in fusion events (Table 1) play roles in preserving genomic stability. These include CAMTA1 [9], ESCO1 [10,11], FOXO3 [12][13][14], GOLGB1 [15], MAP7 [16], REV3L [17], RRM2B [18], USP38 [19], VIM [20], and ZBTB38 [21]. They are involved in DNA replication, ensuring accurate genetic material duplication, and DNA repair mechanisms that fix damage.…”