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Research overview

Dr Rachael Natrajan, Functional Genomics team

The Functional Genomics team integrates molecular pathology with functional genomic approaches to understand how novel somatic DNA alterations control cancer outcomes such as therapy resistance and tumour progression with the overall aim of identify new treatments and biomarkers.
Breast cancer not a single disease, but is rather a collection of several diseases that we know are genetically different from one another. It is now appreciated that this diversity seen between tumours also exists within tumours (intra-tumour heterogeneity). It is also becoming evident that the interaction of different subclones together with their microenvironment fuels progression and resistance to therapy. 
The focus of our work has been to identify and understand the role of recurrent somatic molecular alterations on the progression of breast cancers and resistance to therapy and to identify new ways of treating these patients based on these alterations. We aim to use this information to i) feed into clinical trials and ii) identify and develop new biomarkers that may predict sensitivity or resistance to standard or new therapies.
We apply a multidisciplinary approach to our work, and host within the team cell and molecular biologists, genomics specialists, in vivo specialists and clinicians.

Our success

We have developed novel models and screening approaches to interrogate new driver genes and their functional consequences using both targeted and high-throughput functional genomic approaches coupled with the use of more complex 3-dimensional in vitro cancer and patient derived models.

In addition, we use the novel in vivo intraductal (MIND) model that more accurately recapitulate cell-cell and microenvironmental interactions observed in breast cancer patients. This allows us to functionally dissect drivers of breast cancer disease progression in a more physiologically relevant environment. Our work has identified new genetic dependencies not previously appreciated through the use of conventional in vitro or in vivo systems. 
In particular, we have developed a a 3-dimensional cell culture functional genomics screening platform to model more aggressive tumours in the form of cancer cell line spheroids to identify novel loss of function alterations that drive progression (Maguire and Peck et al J Pathol 2016 and Morrison et al JoVe 2016).

We have gone on to use this platform to identify novel tumour suppressor genes involved in breast cancer progression of therapy resistant disease and identified ways to treat these patients using existing therapies that are FDA approved, meaning we can translate these findings quickly into patient benefit.
We have made significant advances in understanding the role of previously uncharacterised tumour suppressor and oncogenes in breast cancer. For instance, we have identified that novel fusion genes in different subgroups of breast cancer can lead to underlying vulnerabilities (Natrajan et al J Pathol 2014, Naidoo et al Mol Cancer Ther 2018). 

We have identified a new role on tumour progression in aggressive ER+ breast cancer for mutations in components of the spliceosome that lead to global splicing alterations increasing heterogeneity, and can be therapeutically targeted through inhibition of the spliceosome itself (Maguire et al J Pathol 2015, Read et al Endocr Relat Cancer 2018). 
In addition, we have developed novel immunohistochemistry assays for genes that are recurrently mutated in multiple tumour types with aim of developing their utility as biomarkers for patient stratification in clinical trials in particular for the translation of our own work including the development of CDK12 IHC and ARID1A IHC (Naidoo et al Molec Cancer Ther 2018 and Khalique et al J Pathol Clin Res. 2018).
We also have an interest in using image analysis to dissect the microenvironmental composition of breast cancer and evaluate its influences on breast cancer progression (Natrajan et al PLoS Med 2016). 


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