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Exploring the cell extrinsic effects of the RUNX/CBFβ complex in cancer


   Cell Biology of Cancer

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  Prof Karen Blyth, Dr Seth Coffelt  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

The RUNX/CBFβ complex is regarded as one of the most frequent alterations in breast cancer albeit we still have limited knowledge of how it functions in this disease setting. Intriguingly members of the complex have been associated with both a gain of function and loss of function in different contexts and our lab has shown that genetic deletion of either Runx or Cbfβ confers a potent tumour suppressor susceptibility. Furthermore, in addition to intrinsic effects on stemness we find loss of RUNX/CBFβ dramatically alters the transcriptional landscape of tumours suggesting that an important aspect of RUNX activity in tumourigenesis may be to orchestrate the immune microenvironment. This is in keeping with recent studies associating RUNX expression with immune cell infiltration as a prognostic indicator. A better understanding of how RUNX/CBFβ regulates immune infiltration may aid to the design of personalised immune intervention strategies for patients.

The project will capitalise on mouse models of cancer that are established in the lab as well as develop novel models (for example using intraductal delivery of CRISPR guides), profiling tumours with and without RUNX function, using state-of-the-art multi-parameter flow cytometry alongside immunohistochemistry and cytokine arrays. The student will interrogate RNAseq datasets and validate observations in functional assays such as co-culture of cells +/- Runx1/Cbfb with bone marrow derived macrophages (BMDM) and assess bidirectional crosstalk between cell types. Transcriptomic and proteomic interrogation of the secretome will be used to study tumour and BMDM-derived signals, whose function would be testable using genetic modulation and blocking antibody experiments. Correlation between RUNX and immune signatures in human datasets across breast cancer subtypes will help to translate our studies while multiplex imaging and spatial biology will allow us to probe the cellular neighbourhoods at early and late stage of disease progression.

About us

The CRUK Beatson Institute where the lab is based is a world leading cancer research institute, situated in the vibrant city of Glasgow in Scotland and hosting approximately 60 doctoral researchers at any one time. It has an excellent reputation for fundamental cancer research, including world-class metabolism studies and renowned in vivo modelling of tumour growth and metastasis.

To apply, and for further details on the application process, please click ‘Institute website’. Please do not email your CV.

References

Riggio AI, Blyth K. The enigmatic role of RUNX1 in female-related cancers - current knowledge & future perspectives. FEBS J., 2017 Aug; 284(15):2345-2362

Sweeney K, Cameron ER, Blyth K. Complex Interplay between the RUNX transcription Factors and Wnt/β-catenin Pathway in Cancer: A Tango in the Night. Mol Cells. 2020 Feb 29;43(2):188-197

Rooney N, Mason SM, McDonald L, Däbritz JHM, Campbell KJ, Hedley A, Howard S, Athineos D, Nixon C, Clark W, Leach JDG, Sansom OJ, Edwards J, Cameron ER, Blyth K. RUNX1 is a driver of renal cell carcinoma correlating with clinical outcome. Cancer Res, 2020 Jun 1;80(11):2325-2339

Wellenstein, M.D., Coffelt, S.B., Duits, D.E.M. et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature 572, 538–542 (2019)

Fu et al, RUNX regulated immune-associated genes predicts prognosis in breast cancer. Front Genet 2022.


Funding Notes

Students starting in 2023 will receive £21,000 per year for their living expenses. We will also pay their fees to the University of Glasgow.
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