SPECIFICANCER
Led by Professor Stephen Elledge (Brigham and Women’s Hospital, USA).The challenge
SPECIFICANCER is tackling the tissue specificity challenge, set in 2017. In the 30 years prior, extensive research had identified hundreds of genes that, when mutated can cause cancer. Yet the vast majority of these genes only cause cancer in certain parts of the body but not in others – and we don’t know why. By mapping our cells’ cancer drivers and their specificity to different tissues, the team aims to shed light on why many of these mutated genes only cause cancer in select tissues while sparing others. This knowledge could change the way we think about cancer and ultimately allow the development of novel preventative measures, as well as therapeutic interventions specifically tailored to tumour type.
At a glance
SPECIFICANCER is funded by
Team and leadership
SPECIFICANCER is led by:
This multidisciplinary team of scientists from the UK, USA and the Netherlands brings together expertise spanning genetics, epigenetics, bioinformatics, and cell biology to clinical research.
Tackling the tissue specificity challenge
It is well-established that specific mutations can give rise to different types of cancer. For example, mutations in the BRCA1 and BRCA2 genes are implicated in breast and ovarian cancer. These faulty genes are present in nearly all cells within the body, however, despite decades of research, the mechanisms underlying the tissue-specific manifestation of these cancer-causing mutations remain enigmatic.
Central to SPECIFICANCER’s hypothesis is that cancer development exhibits tissue-specific patterns due to differences in the intrinsic molecular programming of cells. Critically, the team are exploring situations where a mutation does not cause cancer, and compare the effects of perturbations in both permissive and non-permissive tissues.
To unravel the mechanisms driving the tissue-specificity of cancer genes the team is exploring the following questions:
- which genes exhibit a robust tissue-specific pattern of mutation in cancer?
- do such patterns stem from active or passive biological processes, and what are the underlying molecular mechanisms?
- do tissue-specific cancer genes exhibit tissue-specific genetic interactions, synthetic lethal relationships, or confer unique vulnerabilities?
- can we utilise these insights to develop new therapeutic strategies?
Towards these aims the team is leveraging publicly available, large-scale genomic data from human primary cancers and cell lines, and conducting comprehensive computational analyses of healthy cells derived from the eight tissue types most commonly associated with cancer development: breast, bowel, lung, skin, kidney, liver, brain and pancreas.
In parallel, SPECIFICANCER is harnessing state-of-the-art techniques in genetic screening, mouse modelling, organoid engineering, genomics, epigenomics and proteomics, and exploring the effects of introducing driver mutations into permissive and non-permissive tissue contexts. The team is focusing on the most potent tissue-specific drivers, from the RAS/MAPK, WNT/β-Catenin, and EZH2/Polycomb pathways.
SPECIFICANCER has made significant progress in exploring tissue specificity of different KRAS mutant alleles, including identifying allele and tissue-specific genetic dependencies. By comparing the common G12D with the more rare A146T, the team also identified the biochemical and structural differences in how these mutant GTPases signal, and that they exert different downstream effects in a tissue specific manner, which reflects their mutational frequencies observed in tumours. In further work the team uncovered specific roles of K-Ras G12D in suppressing miRNA function and the underlying mechanisms.
By performing CRISPR screens in mouse models with an intact immune system, SPECIFICANCER has uncovered the role of the adaptive immune system in driving tumour suppressor inactivation, in a tissue specific manner, in order to allow tumours to avoid immune detection. The team is continuing to explore the role of the immune system in determining the tissue specificity of cancer drivers.
In breast cancer, the team has identified the mechanisms underlying how oestrogen regulates focal amplification to drive oncogene expression, via ERα associated translocations.
The team has also developed tools such as MuSiCal for improved mutational signature analysis, and KaryoTap to allow high throughput aneuploidy detection within tumours from single-cell sequencing data.
The SPECIFICANCER team is now working towards integrating their multi-faceted findings into a comprehensive molecular map in order to uncover the ‘rules of tissue specificity’ and develop AI approaches towards predicting permissiveness or synthetic lethality.
Looking ahead
SPECIFICANCER are transforming our understanding of the mechanisms of oncogenesis, which ultimately could help transform cancer treatment strategies.
Through extensive genetic and molecular studies to understand how each tissue type is uniquely programmed, team SPECIFICANCER hopes to shed light on why some treatments are effective in some tumour types, but not in others. These insights could pinpoint tissue-specific molecular targets, accelerating the development of tailored therapeutic strategies and paving the way for a new era of precision oncology.
