Periodic Reporting for period 1 - IMaP (Imaging tumor vessels as a marker for p53 mutation status in cancer)
Période du rapport: 2020-08-01 au 2022-07-31
As the “guardian of the genome”, the p53 protein helps control cell growth and repair DNA. However, the protein is mutated in over 50% of all cancers. When a p53 mutation occurs, its ability to control cell growth and repair DNA is impaired, allowing cancer cells to grow unchecked. These mutations are also problematic, as they are associated with increased tumor aggressiveness and resistance to conventional cancer treatments. Tailoring cancer treatment based on p53 mutation status is therefore of great interest, as it has the potential to improve treatment responses and outcomes for patients.
Drugs that specifically target and restore the normal function of p53, or counteract the effects of a p53 mutation, are a new type of therapy that can be used to treat cancer based on p53 mutation status. While these p53-targeted treatments hold great promise for personalised treatment based on p53 mutation status, their use is complicated by the fact that p53 mutations can have diverse functional effects on cancer therapy. There is a need to assess the functional impact of p53 mutation status, but this has been challenging due to the lack of surrogate markers linking mutation status to functional outcomes.
Given that p53 can regulate blood vessel growth and that vessel imaging is used clinically to monitor functional response to therapy, we hypothesized that blood vessel features could be a marker that would assess the functional impact of p53 mutation status. This MSCA project therefore aimed to evaluate the links between p53 mutations and various blood vessel features using advanced vessel imaging techniques and p53 response detection methods (Figure 1).
Drugs that specifically target and restore the normal function of p53, or counteract the effects of a p53 mutation, are a new type of therapy that can be used to treat cancer based on p53 mutation status. While these p53-targeted treatments hold great promise for personalised treatment based on p53 mutation status, their use is complicated by the fact that p53 mutations can have diverse functional effects on cancer therapy. There is a need to assess the functional impact of p53 mutation status, but this has been challenging due to the lack of surrogate markers linking mutation status to functional outcomes.
Given that p53 can regulate blood vessel growth and that vessel imaging is used clinically to monitor functional response to therapy, we hypothesized that blood vessel features could be a marker that would assess the functional impact of p53 mutation status. This MSCA project therefore aimed to evaluate the links between p53 mutations and various blood vessel features using advanced vessel imaging techniques and p53 response detection methods (Figure 1).
Our project has led to new technologies and biological insights linking p53 mutation status and blood vessel features. We created and published AQuTAS, an image analysis software to automatically quantify various vascular features from an in vitro sprouting assay (https://doi.org/10.3389/fphar.2022.883083). This software allows rapid quantification of these features and detects known biological changes in response to drugs that affect sprouting. AQuTAS is freely available to other researchers (10.5281/zenodo.6444392) and has already attracted interest from research groups.
Using this approach, we gathered data on how vascular features are affected by p53 mutation status. By combining live imaging and protein-detection methods, we have also characterized how vascular features are affected by p53-targeted therapies that are currently in clinical trials. Our results have identified some of the key molecular pathways involved in this response, and their effects on vascular structure and function. To assess how these in vitro results translate in vivo, we have also optimized an in vivo imaging platform to assess how blood vessel features in tumors expressing different p53 statuses and are developing image analysis pipelines that quantify these features. Our biological findings will be shared in the future with the scientific community through peer-reviewed publications and conferences.
Beyond scientific progress, this project has enhanced the Fellow’s career development by providing skills training in project and personnel management, outreach activities, and funding acquisition. For example, the Fellow supervised several master student projects during the project period and participated in several outreach events to share the work with high school students. These training activities have even led to acquisition of additional independent funding and new collaborations.
Using this approach, we gathered data on how vascular features are affected by p53 mutation status. By combining live imaging and protein-detection methods, we have also characterized how vascular features are affected by p53-targeted therapies that are currently in clinical trials. Our results have identified some of the key molecular pathways involved in this response, and their effects on vascular structure and function. To assess how these in vitro results translate in vivo, we have also optimized an in vivo imaging platform to assess how blood vessel features in tumors expressing different p53 statuses and are developing image analysis pipelines that quantify these features. Our biological findings will be shared in the future with the scientific community through peer-reviewed publications and conferences.
Beyond scientific progress, this project has enhanced the Fellow’s career development by providing skills training in project and personnel management, outreach activities, and funding acquisition. For example, the Fellow supervised several master student projects during the project period and participated in several outreach events to share the work with high school students. These training activities have even led to acquisition of additional independent funding and new collaborations.
We have developed new tools for screening and quantifying vascular features, which could facilitate larger scale screens of vascular effects induced by genetic mutations. We have also uncovered key biological insights into how p53 status and p53-targeted therapies alter blood vessels, enhancing our understanding of how this protein and its mutations can functionally impact response to cancer therapies. These results could lead to the development of surrogate markers linking p53 mutation status to functional outcomes, potentially resulting in more effective and personalized cancer therapies based on p53 status.