Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling.
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Kreuzaler, P., Clarke, M. A., Brown, E. J., Wilson, C., Kortlever, R., Piterman, N., Littlewood, T., et al. (2019). Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling.. Proceedings of the National Academy of Sciences of the United States of America, 116 (44), 22399-22408. https://doi.org/10.1073/pnas.1903485116
Cells with higher levels of Myc proliferate more rapidly and super-competitively eliminate neighbouring cells. Nonetheless, tumour cells in aggressive breast cancers typically exhibit significant and stable heterogeneity in their Myc levels, which correlates with refractoriness to therapy and poor prognosis. This suggests that Myc heterogeneity confers some selective advantage on breast tumour growth and progression. To investigate this, we created a traceable MMTV-Wnt1-driven in vivo chimeric mammary tumour model comprising an admixture of low Myc and reversibly switchable high Myc-expressing clones. We show that such tumours exhibit interclonal mutualism wherein cells with high Myc-expression facilitate tumour growth by promoting pro-tumourigenic stroma yet concomitantly suppress Wnt expression, which renders them dependent for survival on paracrine Wnt provided by low Myc-expressing clones. To identify any therapeutic vulnerabilities arising from such interdependency, we modelled Myc/Ras/p53/Wnt signalling crosstalk as an executable network for low Myc for high Myc clones, and for the two together. This executable mechanistic model replicated the observed interdependence of high-Myc and low-Myc clones and predicted a novel pharmacological vulnerability to co-inhibition of COX2 and MEK. This was confirmed experimentally. Our study illustrates the power of executable models in elucidating mechanisms driving tumour heterogeneity and offers an innovative strategy for identifying novel combination therapies tailored to the oligoclonal landscape of heterogenous tumours.
Animals, Mice, Mammary Neoplasms, Experimental, ras Proteins, Proto-Oncogene Proteins c-myc, Drug Resistance, Neoplasm, Genetic Heterogeneity, Models, Theoretical, Female, Tumor Suppressor Protein p53, Wnt Signaling Pathway
Cancer Research UK (19013)
Cancer Research UK (12077)
External DOI: https://doi.org/10.1073/pnas.1903485116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297821
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