Microscopy reveals how Hippo pathway proteins control gene activity in cancer

Melbourne scientists are teasing out how the “Hippo pathway” works at the molecular level, improving understanding of how it exerts control and its potential as a much-needed treatment for the deadly cancer mesothelioma.

They have filmed, for the very first time, microscopy vision showing the activity of a group of DNA-binding proteins—called TEADs and YAP—which are integral to how the Hippo pathway works.

Professor Kieran Harvey explains the Hippo pathway arose in living beings more than a billion years ago and today it works the same across diverse species from single-celled organisms to mammals, including humans.

It controls how healthy tissues and organs grow, wound healing, how cells proliferate and die when needed, and the Hippo pathway is also implicated when cancer develops and take hold in the body.

Two new drugs acting on the Hippo pathway are currently in first-in-human trials at Peter Mac assessing them as potential treatments for mesothelioma, a hard-to-treat cancer often caused by exposure to asbestos.

“The Hippo pathway controls transcription, which is how the body carries out the instructions from our DNA but how it does this is poorly understood,” says Professor Harvey who has dual appointments at Peter Mac and Monash University.

“In this study we used new microscopy techniques that allowed us to record—for the first time ever—how proteins involved in this signaling pathway work in real time, moving throughout the nucleus of human cells and binding to DNA.

“We studied how these proteins interact with DNA over different timescales and a key finding is that the Hippo pathway dictates which genes are made by cells by controlling the time that TEADs and YAP bind to DNA.”

Notably TEAD1 (one of the TEADs) is known to play a role in the development and progression of mesothelioma, and drugs which inhibit TEADs are being assessed in expectation of a therapeutic benefit.

Another rare cancer epithelioid hemangioendothelioma is caused by the fusion protein YAP-TFE3, and this study also showed this mutated version of YAP binds DNA on longer timescales than YAP or TEADs.

The research, also led by Dr. Benjamin Kroeger from Peter Mac and Monash University, has implications for understanding how these proteins could be targeted by new cancer drugs. The paper has just been published in the journal Science Advances.

“Given its foundational role, we hold great hopes that improving understanding of how the Hippo pathway works will open new avenues for treating mesothelioma and other hard-to-treat cancers,” Professor Harvey says.

The paper is titled “Hippo signaling regulates the nuclear behavior and DNA binding times of YAP and TEAD to control transcription”.

Melbourne scientists are teasing out how the “Hippo pathway” works at the molecular level, improving understanding of how it exerts control and its potential as a much-needed treatment for the deadly cancer mesothelioma.

They have filmed, for the very first time, microscopy vision showing the activity of a group of DNA-binding proteins—called TEADs and YAP—which are integral to how the Hippo pathway works.

Professor Kieran Harvey explains the Hippo pathway arose in living beings more than a billion years ago and today it works the same across diverse species from single-celled organisms to mammals, including humans.

It controls how healthy tissues and organs grow, wound healing, how cells proliferate and die when needed, and the Hippo pathway is also implicated when cancer develops and take hold in the body.

Two new drugs acting on the Hippo pathway are currently in first-in-human trials at Peter Mac assessing them as potential treatments for mesothelioma, a hard-to-treat cancer often caused by exposure to asbestos.

“The Hippo pathway controls transcription, which is how the body carries out the instructions from our DNA but how it does this is poorly understood,” says Professor Harvey who has dual appointments at Peter Mac and Monash University.

“In this study we used new microscopy techniques that allowed us to record—for the first time ever—how proteins involved in this signaling pathway work in real time, moving throughout the nucleus of human cells and binding to DNA.

“We studied how these proteins interact with DNA over different timescales and a key finding is that the Hippo pathway dictates which genes are made by cells by controlling the time that TEADs and YAP bind to DNA.”

Notably TEAD1 (one of the TEADs) is known to play a role in the development and progression of mesothelioma, and drugs which inhibit TEADs are being assessed in expectation of a therapeutic benefit.

Another rare cancer epithelioid hemangioendothelioma is caused by the fusion protein YAP-TFE3, and this study also showed this mutated version of YAP binds DNA on longer timescales than YAP or TEADs.

The research, also led by Dr. Benjamin Kroeger from Peter Mac and Monash University, has implications for understanding how these proteins could be targeted by new cancer drugs. The paper has just been published in the journal Science Advances.

“Given its foundational role, we hold great hopes that improving understanding of how the Hippo pathway works will open new avenues for treating mesothelioma and other hard-to-treat cancers,” Professor Harvey says.

The paper is titled “Hippo signaling regulates the nuclear behavior and DNA binding times of YAP and TEAD to control transcription”.