Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis
Frank Szulzewsky1, Sonali Arora1, Pia Hoellerbauer1,2
1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Abstract:
YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C'-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1-TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.
Insights
YAP1 gene fusions drive cancer by hijacking TEAD-dependent YAP activity, resisting normal pathway regulation. Targeting this YAP-TEAD interaction offers a promising therapeutic strategy for YAP1 fusion-positive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Signaling Pathways
Background:
- The Hippo signaling pathway regulates organ size and is crucial in preventing cancer.
- YAP1 is a key effector of the Hippo pathway, and its gene fusions are implicated in various human cancers.
- Identifying the functional components of YAP1 gene fusions is vital for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the oncogenic potential of specific YAP1 gene fusions (YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, YAP1-SS18).
- To elucidate the molecular mechanisms by which these YAP1 fusions promote tumorigenesis.
- To assess the therapeutic potential of targeting the YAP1-TEAD interaction in YAP1 fusion-driven cancers.
Main Methods:
- Reporter assays to measure transcriptional activity.
- RNA sequencing (RNA-seq) to analyze gene expression changes.
- Chromatin immunoprecipitation sequencing (ChIP-seq) to map protein-DNA interactions.
- Loss-of-function mutations and in vivo/in vitro assays to assess oncogenic activity and therapeutic targeting.
Main Results:
- The studied YAP1 gene fusions (YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, YAP1-SS18) were found to be oncogenic in mouse models.
- All YAP1 fusion proteins exhibited TEAD-dependent YAP activity, with some also utilizing C'-terminal fusion partner functions.
- YAP1 fusion activity was resistant to Hippo pathway inhibition due to constitutive nuclear localization and resistance to degradation.
- Disrupting the TEAD-binding domain inhibited tumor formation in vivo, and inhibiting YAP1-TEAD interaction halted cancer cell growth in vitro.
Conclusions:
- TEAD-dependent YAP activity mediated by YAP1 gene fusions is critical for oncogenesis.
- The constitutive nuclear localization and degradation resistance of YAP1 fusion proteins contribute to their oncogenic function.
- Targeting the YAP1-TEAD interaction presents a viable therapeutic strategy for YAP1 fusion-positive cancers.
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