WEHI researchers have solved a mystery about the most important driver of cancer development - a mutant protein found in half of all cancers - and how it contributes to tumour growth.
The p53 protein is a tumour suppressor that plays a crucial role in preventing the formation of cancerous cells. But when it mutates and becomes defective in cells, the protein can significantly boost a person's risk of cancer development.
In a first, researchers have revealed what behaviours of the mutated protein are critical for fuelling tumour growth – a discovery that could offer new directions for the development of treatment options.
At a glance
- Findings show, for the first time, what traits of the mutant p53 protein are critical for driving cancer growth.
- Mutations of this protein are the biggest driver of cancer development and are found in half of all human cancers around the globe.
- The discovery will help rethink ways to therapeutically treat cancers with p53 mutations, leading to new and improved cancer treatments in future.
When it works properly, the p53 protein serves as a powerful defence mechanism against cancer development by ensuring that cells with compromised DNA either get repaired or removed from our body.
Mutations to this protein can be triggered by a variety of environmental factors – such as exposure to UV radiation – if the body's cell division process goes awry, or if they are genetically inherited.
These abnormalities can lead to a dysfunctional protein that has lost the crucial ability to regulate cellular responses that prevent tumour development and growth. This is known as loss-of-function.
Additionally, some researchers believe these mutations can also lead to a supercharged protein that helps cancerous cells survive and proliferate, known as gain-of-function.
In a new study, published in Cancer Discovery, researchers from WEHI and Trento University (Italy) have answered an age-old question by proving which function helps mutant p53 fuel tumour growth. Associate Professor Gemma Kelly, a co-corresponding author of the paper, said understanding how exactly these mutations contribute to cancer is critical to understanding how to treat patients bearing cancers with the dysfunctional proteins.
"Our study has provided the first evidence to show that it is actually the loss-of-function that impacts cancer growth. We found no evidence of gain-of-function contributing to cancer growth," Assoc Prof Kelly, a Laboratory Head in WEHI's Blood Cells and Blood Cancer Division, said.
"This is significant because until now, there was not much evidence available to properly show whether it is the protein's loss or gain-of-function that spurs cancer growth.
"If you look at all cancers of humanity, about 50% of them have a mutation in p53. Specific cancers like those of the pancreas, lung and breast, commonly have defects in these proteins.
"Our findings have transformed our understanding of these mutations, which help rethink how they can be targeted in the development of new cancer treatments."
Unprecedented data exploration
The study utilised the powerful gene editing tool CRISPR to remove 12 different, mutated versions of the protein with reported gain-of-function effects. Researchers found there was no change to the behaviour of cancer cells, in growth or response to chemotherapy.
Leveraging a significant collaboration with The University of Trento (Italy), the research team was also able to restore p53's normal functions that were lost when the protein mutated. They found this reduced cancer growth in pre-clinical models.
First author Dr Zilu Wang used these models and data from the DepMap database in an in-depth way that had never been done before to consolidate the findings.
"Having these tools at my disposal allowed me to assess 157 different p53 mutations," Dr Wang said.
"The mutations I looked at basically account for at least 90% of human cancers with defects in p53, which will provide crucial insight when informing the development of new anti-cancer strategies."
Future treatments
Co-corresponding author, Professor Andreas Strasser, said the findings could prevent hundreds of millions of dollars being wasted on developing ineffective drugs.
"There is research underway that is working towards finding the first therapeutics to target gain-of-function traits," Prof Strasser, Head of WEHI's Blood Cells and Blood Cancer Division, said.
"Our findings indicate there is no further merit in this therapeutic avenue and the focus needs to shift to restoring the mutant protein's lost function and normal tumour suppressor ability."
The study, 'Loss-of-function but not gain-of-function properties of mutant TP53 are critical for the proliferation, survival and metastasis of a broad range of cancer cells', is published in Cancer Discovery (DOI: 10.1158/2159-8290.CD-23-0402).
Images and video P53 Binding Pictured: The p53 protein (yellow) about to bind to DNA (fuchsia and multicoloured). Malfunctions in the protein impact its ability to adequately repair or remove damaged DNA, which can lead to cancer development. Credit: Etsuko Uno, wehi.tv WEHI Researchers
Associate Professor Gemma Kelly, Professor Andreas Strasser and Dr Zilu Wang
Credit: WEHI Watch and embed this animation explaining how p53 functions
About us:
About WEHI (Walter and Eliza Hall Institute of Medical Research)
WEHI is where the world's brightest minds collaborate and innovate to make life-changing scientific discoveries that help people live healthier for longer. Our medical researchers have been serving the community for more than 100 years, making transformative discoveries in cancers, infectious and immune diseases, developmental disorders, and healthy ageing. WEHI brings together diverse and creative people with different experience and expertise to solve some of the world's most complex health problems. With partners across science, health, government, industry, and philanthropy, we are committed to long-term discovery, collaboration, and translation. At WEHI, we are brighter together.
