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

Prof Karen Blyth & Dr Seth Coffelt

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Labs: In Vivo Cancer Biology and Immune Cells and Metastasis
Duration: 4 years, starting Oct 2023
Closing Date: 6th January 2023

Project Description

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.

For informal enquiries or further details on the project, please contact Prof Karen Blyth (karen.blyth@glasgow.ac.uk)

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Publications

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.

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