Periodic Reporting for period 3 - PROTEUS (Predicting Routes Of Tumour Evolution driven by Unstable genomes and Selection)
Période du rapport: 2022-06-01 au 2023-11-30
Despite progress in cancer drug development, the majority of patients with advanced disease have poor prognoses due to cancer drug resistance. Poor outcome is a result of tumour genomic diversity, which increases the risk of acquiring drug resistance. Longitudinal clinical studies have revealed that tumour DNA copy-number heterogeneity correlates with an increased risk of recurrence and death in non-small cell lung cancer (NSCLC). Current animal models of NSCLC do not reflect the multiple distinct patterns of genome instability and intratumour genetic heterogeneity observed in patients.
The EU-funded PROTEUS project aims to develop mouse lung cancer models that better recapitulate the tumour immune evasion and genome instability processes observed in patients with NSCLC. This will help elucidate the evolutionary patterns of genomic instability, understand mechanisms of immune evasion and test novel therapies aimed at improving patient stratification, treatment and survival.
The EU-funded PROTEUS project aims to develop mouse lung cancer models that better recapitulate the tumour immune evasion and genome instability processes observed in patients with NSCLC. This will help elucidate the evolutionary patterns of genomic instability, understand mechanisms of immune evasion and test novel therapies aimed at improving patient stratification, treatment and survival.
During the first half of the project we have generated multiple new mouse models to investigate lung tumour development and the mechanisms of tumour immune evasion and treatment resistance observed in patients with lung cancer. One of the mouse models generated expresses APOBEC3B, a protein that has been shown to induce mutations in multiple human cancers. Investigations using the novel APOBEC3B expressing mouse model has revealed that although APOBEC3B expression is detrimental to tumour initiation, subclonal APOBEC3B expression promotes tumour progression in the presence of drug treatment (Mayekar et al, biorxiv 2020)
Using new techniques to measure the effects on tumour developement of cancer genes identified in the associated TRACERx studies, we have uncovered multiple different roles played by these genes in tumour evolution; they can impact the chance of a cell becoming a tumour, alter the growth of the tumour, and even change the likelihood of acquiring further changes during the tumour growth (Cai et al, Cancer Discovery 2021). We have also been able to demonstrate that part of the DNA copy number gains or losses occurring in cancer are recurrent and most likely describe tumour evolutionary pathways (Watkins et al, Nature 2020). We are currently developing further methods to characterise and model some of these recurrent DNA copy number losses.
Using new techniques to measure the effects on tumour developement of cancer genes identified in the associated TRACERx studies, we have uncovered multiple different roles played by these genes in tumour evolution; they can impact the chance of a cell becoming a tumour, alter the growth of the tumour, and even change the likelihood of acquiring further changes during the tumour growth (Cai et al, Cancer Discovery 2021). We have also been able to demonstrate that part of the DNA copy number gains or losses occurring in cancer are recurrent and most likely describe tumour evolutionary pathways (Watkins et al, Nature 2020). We are currently developing further methods to characterise and model some of these recurrent DNA copy number losses.
In Watkins et al (Nature 2020) we identified common, cancer specific, recurrent changes in DNA copy numbers. The same DNA copy number alterations were observed in distinct regions within individual tumours indicating selection pressures in the tumour or tumour environment resulting in convergent evolution.
Multiple studies are beginning to elucidate the complex interplay between different tumour mutations within the same tumour. In Cai et al, Cancer Discovery 2021, we show that some of these co-occurring mutations have the potential to generate rare, surprisingly large, tumours whereas others increase tumour growth or tumour initiation. Our results demonstrate the impact rare tumour suppressors can have on tumour evolution.
The phenomenon of mixed tumour responses in response to targeted therapy is a clinical concern. In Hobor et al (Nature Communications 2024) we show that concomitant whole genome doubling and TP53-pathway loss-of-function leads to an increased risk of mixed treatment response. Our data suggests that patients that have tumours that are both whole genome doubled and have lost TP53 function are at a higher risk of progressing while on treatment due to increased genomic instability.
It has long been suggested that particulate matter measuring ≤2.5 μm (PM2.5) is associated with an increased lung cancer risk. In Hill et al (Nature 2023) we demonstrated that particulate matter promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations. Using mouse models developed in this project, our data further revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This inflammatory reaction leads to an increased proliferation of the mutated cells and promotes lung cancer formation. Our data demonstrates the need for public health policy initiatives to reduce the levels of air pollution to reduce lung cancer incidence.
We expect that the knowledge gained in this project will help elucidate the evolutionary patterns of genomic instability, understand mechanisms of immune evasion and test novel therapies aimed at improving patient stratification, treatment and survival.
Multiple studies are beginning to elucidate the complex interplay between different tumour mutations within the same tumour. In Cai et al, Cancer Discovery 2021, we show that some of these co-occurring mutations have the potential to generate rare, surprisingly large, tumours whereas others increase tumour growth or tumour initiation. Our results demonstrate the impact rare tumour suppressors can have on tumour evolution.
The phenomenon of mixed tumour responses in response to targeted therapy is a clinical concern. In Hobor et al (Nature Communications 2024) we show that concomitant whole genome doubling and TP53-pathway loss-of-function leads to an increased risk of mixed treatment response. Our data suggests that patients that have tumours that are both whole genome doubled and have lost TP53 function are at a higher risk of progressing while on treatment due to increased genomic instability.
It has long been suggested that particulate matter measuring ≤2.5 μm (PM2.5) is associated with an increased lung cancer risk. In Hill et al (Nature 2023) we demonstrated that particulate matter promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations. Using mouse models developed in this project, our data further revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This inflammatory reaction leads to an increased proliferation of the mutated cells and promotes lung cancer formation. Our data demonstrates the need for public health policy initiatives to reduce the levels of air pollution to reduce lung cancer incidence.
We expect that the knowledge gained in this project will help elucidate the evolutionary patterns of genomic instability, understand mechanisms of immune evasion and test novel therapies aimed at improving patient stratification, treatment and survival.