Requirement for YAP1 signaling in myxoid liposarcoma

Abstract

Myxoid liposarcomas ( MLS ), malignant tumors of adipocyte origin, are driven by the FUS ‐ DDIT 3 fusion gene encoding an aberrant transcription factor. The mechanisms whereby FUS ‐ DDIT 3 mediates sarcomagenesis are incompletely understood, and strategies to selectively target MLS cells remain elusive. Here we show, using an unbiased functional genomic approach, that FUS ‐ DDIT 3‐expressing mesenchymal stem cells and MLS cell lines are dependent on YAP 1, a transcriptional co‐activator and central effector of the Hippo pathway involved in tissue growth and tumorigenesis, and that increased YAP 1 activity is a hallmark of human MLS . Mechanistically, FUS ‐ DDIT 3 promotes YAP 1 expression, nuclear localization, and transcriptional activity and physically associates with YAP 1 in the nucleus of MLS cells. Pharmacologic inhibition of YAP 1 activity impairs the growth of MLS cells in vitro and in vivo . These findings identify overactive YAP 1 signaling as unifying feature of MLS development that could represent a novel target for therapeutic intervention.

Myxoid liposarcoma: it's a hippo's world

“…RASS4 associates with mammalian STE20‐like protein kinase 1 (MST1) as an inhibitory complex to further reduce Hippo activation and thereby promotes cell cycle progression and evasion of cell senescence (Crose et al , ). In the present study, Trautmann et al () show that FUS:DDIT3 co‐localizes with YAP1 in the nucleus of MLS cells, which may contribute to stabilization of active YAP1 in the nucleus. The mechanism by which FUS:DDIT3 acts to achieve/maintain YAP1 activation remains to be experimentally elucidated.…”

“…Trautmann et al () argue that the identification of signaling pathways, that are essential in cells expressing chimeric fusion oncoproteins, represents a highly promising strategy to selectively target these cancer cells. Their present study (Trautmann et al , ) utilized a drop‐out RNAi screen in FUS:DDIT3‐expressing, immortalized human mesenchymal stem cell lines as an unbiased functional genomic approach to reveal that FUS:DDIT3‐expressing cells require Yes‐associated protein 1 (YAP1), a downstream nuclear effector of the Hippo signaling pathway, to maintain viability and cell growth. Among liposarcoma cell lines, YAP1 expression was detected in one pleomorphic and three MLS cell lines.…”

“…In fact, silencing of YAP1 resulted in G1 arrest, senescence, and apoptosis, supporting a dependence on YAP1 of FUS:DDIT3‐positive MLS cell lines. Trautmann et al () went on to further examine the relationship between FUS:DDIT3 and increased YAP1 activity in MLS by overexpressing FUS:DDIT3 in human mesenchymal stem cell lines. This led to expression, nuclear translocation, and activation of YAP1 and of its effectors PLK1 and FOXM1.…”

“…Several kinases in the Hippo network might serve as therapeutic targets, but most of them are tumor suppressors and restoring lost tumor suppressor function may prove to be difficult. Trautmann et al () use verteporfin, a photosensitizer, which is in clinical use to treat patients with macular degeneration. Verteporfin binds to YAP1 altering its conformation and preventing it from binding to TEAD transcription factors (Deel et al , ).…”

“…Yet, their discovery in leukemias and sarcomas has not translated into improvements in treatment and survival rates, because they act as transcriptional dysregulators and successful pharmacological modulation using small molecules has not been possible thus far (Parker & Zhang, 2013). Trautmann et al (2019) argue that the identification of signaling pathways, that are essential in cells expressing chimeric fusion oncoproteins, represents a highly promising strategy to selectively target these cancer cells. Their present study (Trautmann et al, 2019) utilized a drop-out RNAi screen in FUS:DDIT3-expressing, immortalized human mesenchymal stem cell lines as an unbiased functional genomic approach to reveal that FUS:DDIT3-expressing cells require Yesassociated protein 1 (YAP1), a downstream nuclear effector of the Hippo signaling pathway, to maintain viability and cell growth.…”