A project funded by the EHE Foundation, the EHE Rare Cancer Charity (UK), and the EHE Rare Cancer Foundation Australia, and led by Dr. Ryan Kanai in the Lamar Lab, was recently published in Cancers, revealing a surprising new role for AMPK in controlling the growth of EHE cells. 

Dr. Kanai set out to find molecular pathways that could block the activity of TAZ-CAMTA1, the fusion protein that drives EHE. Initially, the project proposed to use fibroblasts expressing TAZ-CAMTA1 because there were no EHE cell lines available. Using engineered fibroblast cells, his team found that activating AMP kinase (AMPK), a master regulator of cellular energy, could suppress TAZ-CAMTA1 activity.

Subsequently, EHE cell lines were developed in Dr. Brian Rubin’s lab, allowing the team to test AMPK-activating drugs directly on EHE cells. These drugs slowed EHE cell growth by shutting down the mTOR pathway, providing new evidence to support the use of Sirolimus (an mTOR inhibitor) in EHE. Interestingly, the study also revealed a second, unexpected effect of AMPK activation. 

Although in fibroblasts AMPK suppressed TAZ-CAMTA1 activity, in EHE cells, it actually increased TAZ-CAMTA1 activity, paradoxically slowing the growth of the EHE cells. This surprising result suggests that EHE cells depend on a delicate balance of TAZ-CAMTA1 activity to proliferate and survive: too little activity halts their growth, but too much may also be detrimental to them. 

These findings raise the intriguing possibility that the transition from indolent to aggressive EHE may depend on whether EHE cells can adapt to or overcome the harmful effects of excessive TAZ-CAMTA1 activity. 

Collectively, this work identifies AMPK-activating drugs as potential therapeutic candidates for EHE. It also provides new insights into the complex role of TAZ-CAMTA1- insights that could be leveraged diagnostically to predict disease progression or therapeutically to limit it.