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WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma.

ABSTRACT: Epithelioid hemangioendothelioma (EHE) is a poorly understood and devastating vascular cancer. Sequencing of EHE has revealed a unique gene fusion between the Hippo pathway nuclear effector TAZ (WWTR1) and the brain-enriched transcription factor CAMTA1 in ∼90% of cases. However, it remains unclear whether the TAZ-CAMTA1 gene fusion is a driver of EHE, and potential targeted therapies are unknown. Here, we show that TAZ-CAMTA1 expression in endothelial cells is sufficient to drive the formation of vascular tumors with the distinctive features of EHE, and inhibition of TAZ-CAMTA1 results in the regression of these vascular tumors. We further show that activated TAZ resembles TAZ-CAMTA1 in driving the formation of EHE-like vascular tumors, suggesting that constitutive activation of TAZ underlies the pathological features of EHE. We show that TAZ-CAMTA1 initiates an angiogenic and regenerative-like transcriptional program in endothelial cells, and disruption of the TAZ-CAMTA1-TEAD interaction or ectopic expression of a dominant negative TEAD in vivo inhibits TAZ-CAMTA1-mediated transformation. Our study provides the first genetic model of a TAZ fusion oncoprotein driving its associated human cancer, pinpointing TAZ-CAMTA1 as the key driver and a valid therapeutic target of EHE.

SUBMITTER: Driskill JH

PROVIDER: S-EPMC8015719 | biostudies-literature |

REPOSITORIES: biostudies-literature

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<i>WWTR1</i>(TAZ)-<i>CAMTA1</i> gene fusion is sufficient to dysregulate YAP/TAZ signaling and drive epithelioid hemangioendothelioma tumorigenesis.

Project description:Epithelioid hemangioendothelioma (EHE) is a genetically homogenous vascular sarcoma that is a paradigm for TAZ dysregulation in cancer. EHE harbors a WWTR1(TAZ)-CAMTA1 gene fusion in >90% of cases, 45% of which have no other genetic alterations. In this study, we used a first of its kind approach to target the Wwtr1-Camta1 gene fusion to the Wwtr1 locus, to develop a conditional EHE mouse model whereby Wwtr1-Camta1 is controlled by the endogenous transcriptional regulators upon Cre activation. These mice develop EHE tumors that are indistinguishable from human EHE clinically, histologically, immunohistochemically, and genetically. Overall, these results demonstrate unequivocally that TAZ-CAMTA1 is sufficient to drive EHE formation with exquisite specificity, as no other tumor types were observed. Furthermore, we fully credential this unique EHE mouse model as a valid preclinical model for understanding the role of TAZ dysregulation in cancer formation and for testing therapies directed at TAZ-CAMTA1, TAZ, and YAP/TAZ signaling.

| S-EPMC8015722 | biostudies-literature

Monoclonality of multifocal epithelioid hemangioendothelioma of the liver by analysis of WWTR1-CAMTA1 breakpoints.

Project description:Similar to other vascular tumors, epithelioid hemangioendothelioma (EHE) can have multifocal presentation in up to 50% of cases. However, whether multifocal EHE represents an unusual pattern of metastasis or multiple separate primary tumors remains to be elucidated. Our recent identification of a WWTR1-CAMTA1 fusion as the genetic hallmark of EHE irrespective of anatomic location was used to clarify this question by comparing the similarity of translocation breakpoints. In our previous study, we found variability of the fusion transcripts of the t(1;3)(p36;q25) translocation among different patients with EHE. Thus, we undertook a molecular analysis of six samples from two patients with multicentric hepatic EHE to test our hypothesis that the presence of identical breakpoints in WWTR1 and CAMTA1 support the monoclonal nature of multifocal EHE. Using reverse transcription-polymerase chain reaction (RT-PCR) and subsequent sequencing, we confirmed an identical WWTR1-CAMTA1 fusion transcript product from different nodules in each patient. Our results confirm that multifocal EHE are monoclonal and thus represent metastatic implants of the same neoplastic clone rather than a "field-effect" or synchronous occurrence of multiple neoplastic clones.

| S-EPMC3361903 | biostudies-literature

Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ-CAMTA1 Fusion Driven Sarcoma.

Project description:The activities of YAP and TAZ, the end effectors of the Hippo pathway, are consistently altered in cancer, and this dysregulation drives aggressive tumor phenotypes. While the actions of these two proteins aid in tumorigenesis in the majority of cancers, the dysregulation of these proteins is rarely sufficient for initial tumor development. Herein, we present a unique TAZ-driven cancer, epithelioid hemangioendothelioma (EHE), which harbors a WWTR1(TAZ)-CAMTA1 gene fusion in at least 90% of cases. Recent investigations have elucidated the mechanisms by which YAP/TAP-fusion oncoproteins function and drive tumorigenesis. This review presents a critical evaluation of this recent work, with a particular focus on how the oncoproteins alter the normal activity of TAZ and YAP, and, concurrently, we generate a framework for how we can target the gene fusions in patients. Since EHE represents a paradigm of YAP/TAZ dysregulation in cancer, targeted therapies for EHE may also be effective against other YAP/TAZ-dependent cancers.

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Fluorescence in situ hybridization for WWTR1-CAMTA1 has higher sensitivity and specificity for epithelioid hemangioendothelioma diagnosis.

Project description:Epithelioid hemangioendothelioma (EHE) is a rare medium-to-low-grade malignant vascular tumor characterized by vascular differentiation along with specific morphological and genetic alterations. Approximately 90% and 5% of EHE cases are associated with the WWTR1-CAMTA1 and YAP1/TFE3 fusion gene, respectively. Therefore, nuclear CAMTA1 protein expression is considered to be an effective marker for EHE diagnosis. However, the specificity and reliability of this approach have recently been put into question. The purpose of this study was to compare the detection of CAMTA1 expression in cases of EHE and histologic mimics using fluorescence in situ hybridization (FISH) and conventional protein immunohistochemistry via hematoxylin and eosin staining. Fifteen EHE and 37 histologic mimic samples were immunohistochemically stained with polyclonal anti-CAMTA1 antibody to evaluate the nuclear protein expression level of CAMTA1. In addition, 15 EHE samples and 10 vascular tumor samples were subjected to FISH to detect the WWTR1-CAMTA1 fusion gene. Histologically, EHE typically showed a mucous hyaline or cartilaginous stroma, often forming a primitive vascular lumen, and expressed vascular endothelial markers. Twelve of the 15 EHE samples showed positive nuclear CAMTA1 expression with immunohistochemistry, whereas six of the 37 histologic mimics showed positive nuclear expression. FISH detected a red-green signal fusion in 14 of the 15 cases of EHE, but in none of the 10 vascular tumors. These results indicate that CAMTA1 is an effective and useful EHE marker, but that FISH fusion gene detection has better diagnostic value and clinical significance.

| S-EPMC7476104 | biostudies-literature

A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites.

Project description:The classification of epithelioid vascular tumors remains challenging, as there is considerable morphological overlap between tumor subtypes, across the spectrum from benign to malignant categories. A t(1;3)(p36.3;q25) translocation was reported in two cases of epithelioid hemangioendothelioma (EHE), however, no follow-up studies have been performed to identify the gene fusion or to assess its prevalence in a larger cohort of patients. We undertook a systematic molecular analysis of 17 EHE, characterized by classic morphological and immunophenotypic features, from various anatomical locations and with different malignant potential. For comparison, we analyzed 13 epithelioid hemangiomas, five epithelioid angiosarcomas, and four epithelioid sarcoma-like EHE. A fluorescence in situ hybridization (FISH) positional cloning strategy, spanning the cytogenetically defined regions on chromosomes 1p36.3 and 3q25, confirmed rearrangements in two candidate genes from these loci in all EHE cases tested. None of the other benign or malignant epithelioid vascular tumors examined demonstrated these abnormalities. Subsequent reverse transcription-polymerase chain reaction (RT-PCR) confirmed in three EHE the WWTR1-CAMTA1 fusion product. CAMTA1 and WWTR1 have been previously shown to play important roles in oncogenesis. Our results demonstrate the presence of a WWTR1-CAMTA1 fusion in all EHE tested from bone, soft tissue, and visceral location (liver, lung) in keeping with a unique and specific pathological entity. Thus, FISH or RT-PCR analysis for the presence of WWTR1-CAMTA1 fusion may serve as a useful molecular diagnostic tool in challenging diagnoses.

| S-EPMC3264678 | biostudies-literature

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

Project description:PurposeA 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.Experimental designWe 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.ResultsWe 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, 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.ConclusionsCollectively, 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.

| S-EPMC9306355 | biostudies-literature

Mechanism of action of a WWTR1(TAZ)-CAMTA1 fusion oncoprotein.

Project description:The WWTR1 (protein is known as TAZ)-CAMTA1 (WC) fusion gene defines epithelioid hemangioendothelioma, a malignant vascular cancer. TAZ (transcriptional coactivator with PDZ binding motif) is a transcriptional coactivator and end effector of the Hippo tumor suppressor pathway. It is inhibited by phosphorylation by the Hippo kinases LATS1 and LATS2. Such phosphorylation causes cytoplasmic localization, 14-3-3 protein binding and the phorphorylation of a terminal phosphodegron promotes ubiquitin-dependent degradation (the phosphorylation of the different motifs has several effects). CAMTA1 is a putative tumor suppressive transcription factor. Here we demonstrate that TAZ-CAMTA1 (TC) fusion results in its nuclear localization and constitutive activation. Consequently, cells expressing TC display a TAZ-like transcriptional program that causes resistance to anoikis and oncogenic transformation. Our findings elucidate the mechanistic basis of TC oncogenic properties, highlight that TC is an important model to understand how the Hippo pathway can be inhibited in cancer, and provide approaches for targeting this chimeric protein.

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Epithelioid hemangioendothelioma: a case report.

Project description:Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor with limited clinical data that can guide treatment choices. The diagnosis of EHE is based on its unique histological, immunohistochemical, and molecular characteristics. Differential diagnoses are broad and include autoimmune diseases. Treatments include hepatic resection, liver transplantation, systemic/regional chemotherapy, and radiotherapy. We describe EHE in a patient with weight loss and general weakness. The prognosis of EHE is variable, with few cases demonstrating an indolent clinical course, whereas others tend to metastasize. In our case, hepatic EHE had metastasized to the lungs and brain. Histopathological examination of the liver tissue revealed an epithelial hemangioendothelioma. On CK7 staining, hepatocytes were clearly reactive and arranged in the plates (CK7: negative), with positive immunohistochemical staining for CD34 (CD34: positive) alone. Surveillance was conducted and the clinical course was better than expected, probably due to her relatively good general condition, the lack of genetic factors associated with her familial medical history, and normal levels of tumor markers such as α-fetoprotein and carcinoembryonic antigen (CEA). During a follow-up examination, she was asymptomatic with a healthy general appearance. The prognosis of EHE is variable, with few cases demonstrating an indolent clinical course, whereas others tend to metastasize. The treatment method for EHE should be determined according to the patient's condition.

| S-EPMC11292091 | biostudies-literature

Epithelioid Hemangioendothelioma of the Foot.

Project description:We describe the case of an 18-year-old male Army reservist presenting with left lower extremity pain for which he was initially diagnosed with a stress injury. After failing conservative treatment, a radiograph was obtained showing a "lacelike" appearance of the medullary bone in the foot and ankle. Magnetic resonance imaging subsequently demonstrated widespread polyostotic marrow replacement with coarsened trabeculations. A biopsy was obtained which diagnosed the patient with polyostotic epithelioid hemangioendothelioma which is the most common malignant vascular tumor of bone. The patient ultimately underwent a below the knee amputation once computed tomography of the chest, abdomen, and pelvis excluded distant metastatic disease. It is important for radiologists to be aware of this diagnosis because osseous epithelioid hemangioendothelioma can present like a stress injury and be mistaken for a less serious diagnosis while potentially having visceral involvement.

| S-EPMC9063823 | biostudies-literature

scRNAseq of TAZ-CAMTA1 expressing endothelial cells in vivo

Project description:TAZ-CAMTA1 is a defining genetic aberration in the vascular cancer epithelioid hemangioendothelioma. We generated a novel transgenic mouse that expresses TAZ-CAMTA1 in endothelial cells. These mice develop vascular tumors in the lung and die by average on day 40. We isolated GFP + endothelial cells from three five-week old TRE-TAZ-CAMTA1;Cdh5-tTA;TRE-GFP mice and subjected these endothelial cells to scRNA-seq via the 10X genomics platform

2021-05-23 | GSE156803 | GEO

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