YAP, TAZ, and Hippo-Dysregulating Fusion Proteins in Cancer

Abstract

Gene fusions are well-known drivers of cancer and are potent targets for molecular therapy. An emerging spectrum of human tumors harbors recurrent and pathognomonic gene fusions that involve the transcriptional coactivator YAP1 (which encodes the protein YAP) or its paralog WWTR1 (which encodes the protein TAZ). YAP and TAZ are frequently activated in cancer and are the transcriptional effectors of the Hippo pathway, a highly conserved kinase cascade that regulates diverse functions such as organ size, development, and homeostasis. In this review, we discuss the tumors that have YAP, TAZ, or other Hippo-dysregulating fusion proteins; the mechanisms of these fusion proteins in driving their respective tumors; and the potential vulnerabilities of these chimeric oncoproteins across cancers of many origins. Furthermore, as new YAP1 and WWTR1 gene fusions are discovered, we provide a framework to predict whether the resulting protein product is likely to be oncogenic.

Keywords: Hippo pathway; WWTR1/TAZ; YAP1; cancer; gene fusions; sarcoma.

Figure 1

Tumors with reported YAP/TAZ fusion proteins. Tumor names are shown adjacent to their corresponding YAP/TAZ fusion protein(s). Panels a–f show the variability of histology of YAP-/TAZ-fusion-associated hemangioendotheliomas. (a) TAZ::CAMTA1 epithelioid hemangioendothelioma (EHE) showing epithelioid tumor cells with pale eosinophilic cytoplasm, occasional intracytoplasmic vacuoles, open chromatin, and inconspicuous nucleoli arranged in clusters and cords against background myxohyaline stroma. (b) TAZ::ACTL6A EHE showing epithelioid tumor cells with granular eosinophilic cytoplasm, frequent intracytoplasmic vacuoles, vesicular chromatin, and variably prominent nucleoli arranged in small nests and solid sheets set in a collagenous to fibrous stroma. (c) TAZ::MAML2 EHE showing epithelioid cells with pale eosinophilic cytoplasm, occasional intracytoplasmic vacuoles, and open chromatin arranged haphazardly against background myxohyaline stroma and admixed with hemosiderin and occasional erythrocytes. (d) YAP::TFE3 EHE displaying large epithelioid cells with voluminous glassy cytoplasm and variably prominent nucleoli arranged in nests and solid sheets. (e) YAP::MAML2 composite hemangioendothelioma containing an admixture of arborizing vascular channels and solid areas of uniform hyperchromatic ovoid to cuboidal tumor cells. (f) YAP::MAML2 retiform hemangioendothelioma consisting of arborizing and elongated vascular channels lined by hobnail endothelial cells dissecting through dermal connective tissue.

Figure 2

The Hippo pathway in cancer. YAP and TAZ are phosphorylated (represented by P) by the core kinase cascade, enriched in the cytoplasm, and degraded. When not phosphorylated, YAP and TAZ are in the nucleus, where they activate transcription. YAP and TAZ are strongly influenced by extracellular activity, which can promote or inhibit their activity. Tumor suppressors that are frequently mutated in cancer to lead to the activation of YAP and TAZ are highlighted in blue. Oncogenes that frequently exhibit copy number gains in cancer are in red. The component in gray is not frequently mutated in cancer but is discussed in this review.

Figure 3

The structure and function of YAP/TAZ fusion proteins. YAP/TAZ fusion proteins are localized to the nucleus, are resistant to Hippo-driven degradation, and drive an oncogenic program. The canonical C-terminal fusion partner may participate in phase condensates to hyperactivate transcription and inhibit Polycomb-dependent gene repression (PRC2). Proposed therapeutic inhibitors of YAP/TAZ fusion oncoproteins are shown in red. Abbreviations: IDR, intrinsically disordered region; NLS, nuclear localization signal; TAD, transcription activation domain; TBD, TEAD-binding domain.