Sustained Activation of Endothelial YAP1 Causes Epithelioid Hemangioendothelioma

Response by Jung et al to Letter Regarding Article, “Sustained Activation of Endothelial YAP1 Causes Epithelioid Hemangioendothelioma”

“…17 Consistent with the study by Driskill et al, 17 we observed enrichment in the YAP1 target gene signature, upregulation of the vast majority of mitotic cell cycle genes, and expression of known epithelioid hemangioendothelioma markers in endothelial YAP1-expressing intravascular epithelioid hemangioendothelioma lesions (Figure [D through F] in the study by Jung et al). 16 We also observed highly mitotic Cdh5 + (Cadherin 5) endothelial cells in intravascular epithelioid hemangioendothelioma lesions, suggesting a cell autonomous role of YAP1 in endothelial cell proliferation (Figure [E and F] in the study by Jung et al). 16 These studies 16,17 support a model in which endothelial cells expressing stable and active YAP1/WWTR1/WWTR1-CAMTA1 give rise to a highly mitotic form of intravascular epithelioid hemangioendothelioma in the large vessels, like the pulmonary artery, leading to severe deep vessel occlusion—a clinical phenomenon first described by Weiss-Enzinger 1 and Dail-Liebow.…”

“…16 These studies 16,17 support a model in which endothelial cells expressing stable and active YAP1/WWTR1/WWTR1-CAMTA1 give rise to a highly mitotic form of intravascular epithelioid hemangioendothelioma in the large vessels, like the pulmonary artery, leading to severe deep vessel occlusion—a clinical phenomenon first described by Weiss-Enzinger 1 and Dail-Liebow. 12 Taken together, our study 16 demonstrates that sustained activation of endothelial YAP1 signaling in mice recapitulates human intravascular epithelioid hemangioendothelioma at genetic, histological, and clinical levels.…”

“…Hence, the goal of our study 16 is as stated: “Despite the potential importance of dysregulated Hippo/YAP signaling in epithelioid hemangioendothelioma, it has remained unclear whether YAP1 activation alone is sufficient to drive the formation of epithelioid hemangioendothelioma in vivo.” Endothelial cell–specific activation of YAP1 alone (YAP 5SA ) in adult mice resulted in formation of occlusive intravascular tumors arising from the endothelium of the pulmonary artery, the aorta, and the right atrium that histologically resembled epithelioid hemangioendothelioma, including features of epithelioid or spindled endothelial cells with cytoplasmic vacuoles, embedded in a myxohyaline stroma (Figure [B and C] in the study by Jung et al). 16 Consistent with our observations, a recent elegant study 17 from Duojia Pan’s laboratory demonstrated that endothelial cell–specific activation of WWTR1 alone (TAZ 4SA ) or WWTR1-CAMTA1 (calmodulin-binding transcription activator 1) fusion in mice promotes the formation of occlusive intravascular tumors arising from the endothelium of the pulmonary artery that histologically resembled epithelioid hemangioendothelioma, including epithelioid or spindled endothelial cells with cytoplasmic vacuoles (Figures 1, 2, and 4 and Figure I in the Data Supplement in the study by Driskill et al). 17 In addition, WWTR1 alone (TAZ 4SA ) or WWTR1-CAMTA1 fusion activates expression of the YAP1 target gene signature in highly proliferative endothelial cells forming intravascular epithelioid hemangioendothelioma (Figures 4 and 6 and Figure III in the Data Supplement in the study by Driskill et al).…”

Pathological MAPK activation–mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib

“…Immunofluorescent staining. Slides with tissue sections were processed for immunofluorescent staining as previously described (105,106). Briefly, after deparaffinization, the slides were immersed in a chamber containing sodium citrate buffer (10 mM sodium citrate and 0.05% Tween-20, pH 6), and heat-induced antigen retrieval was performed using an antigen retriever (Aptum Biologics) or alternately using a commercial pressure cooker at high setting for 15 minutes.…”

Letter by Seavey and Rubin Regarding Article, “Sustained Activation of Endothelial YAP1 Causes Epithelioid Hemangioendothelioma”

“…We have read the published article "Sustained Activation of Endothelial YAP1 Causes Epithelioid Hemangioendothelioma" by Jung et al 1 and have substantial concerns with the conclusions of this publication. The reported mouse model does not recapitulate epithelioid hemangioendothelioma (EHE) that is driven by the YAP1-TFE3 (Yes-associated protein 1-transcription factor E3) fusion gene genetically, clinically, or histologically.…”