Understanding the role of the BRAFV600E oncoprotein in colorectal cancer initiation and metastasis

Project Summary

The 1799T>A substitution in the BRAF proto-oncogene, which produces the BRAF^V600E oncoprotein, occurs in about 11% of colorectal cancers (CRC). This mutation confers a poor prognosis and in the case of the microsatellite stable (MSS) subgroup even the worst prognosis to CRC patients. This can be explained by the refractoriness of these CRCs to chemo- and targeted therapy, e.g. anti-EGFR antibodies, and their early, aggressive and distinct metastatic spreading pattern.

Using complementary approaches involving conditional isogenic cell line and animal models, incl. intestinal organoids, and clinical specimen, we aim to decipher the molecular and cellular mechanisms by which BRAF^V600E expressing CRCs initiate metastasis. In addition, we investigate how BRAF inhibitors interfere with the signaling network of colorectal cancer cells.

Further reading

1. Herr, R., S. Halbach, M. Heizmann, H. Busch, M. Boerries and T. Brummer (2018). “BRAF inhibition upregulates a variety of receptor tyrosine kinases and their downstream effector Gab2 in colorectal cancer cell lines.” Oncogene 37(12): 1576-1593.
2. Diedrich, B., K. T. Rigbolt, M. Roring, R. Herr, S. Kaeser-Pebernard, C. Gretzmeier, R. F. Murphy, T. Brummer and J. Dengjel (2017). “Discrete cytosolic macromolecular BRAF complexes exhibit distinct activities and composition.” EMBO J 36(5): 646-663.
3. Herr, R. and T. Brummer (2015). “BRAF inhibitors in colorectal cancer: toward a differentiation therapy?” Molecular & Cellular Oncology 2: 4, e1002709.
4. Herr, R., M. Kohler, H. Andrlova, F. Weinberg, Y. Moller, S. Halbach, L. Lutz, J. Mastroianni, M. Klose, N. Bittermann, S. Kowar, R. Zeiser, M. A. Olayioye, S. Lassmann, H. Busch, M. Boerries and T. Brummer (2015). “B-Raf Inhibitors Induce Epithelial Differentiation in BRAF-Mutant Colorectal Cancer Cells.” Cancer Res 75(1): 216-229.