Transcriptional and epigenetic mechanisms controlling breast cancer biology
Research in the Siersbaek lab is focused on understanding the transcriptional and epigenetic mechanisms that control breast cancer progression. We integrate functional approaches (e.g., CRISPR, degron systems, small molecule inhibitors) and genomics/proteomics technologies (including single-cell technologies) in cell lines, mouse xenograft models, patient-derived tumour organoids and patient samples to understand how transcriptional regulators work together to control cancer biology and ultimately disease progression. The long-term goal is to uncover targetable pathways to ultimately benefit patient care.
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Although mutations are key initiating events in cancer development, it is becoming increasingly clear that alterations in transcriptional and epigenetic mechanisms are key drivers of cancer progression. These transcriptional addictions represent an important class of targetable mechanisms with great therapeutic potential that we are pursuing in the Siersbaek lab.
Breast cancer is the most common type of cancer affecting 1 in 8 women during their lifetime. We are particularly interested in the role of steroid hormone receptors (estrogen receptor alpha and the glucocorticoid receptor) and the key oncoprotein MYC in regulating the transcriptional and epigenetic mechanisms controlling this disease. To understand the role of these key transcription factors in breast cancer, we employ a range of omics technologies such as chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), quantitative multiplexed rapid immunoprecipitation mass spectrometry of endogenous proteins (qPLEX-RIME), and single-cell technologies in both cell lines and mouse models of breast cancer as well as patient-derived tumour organoids and patient samples. The ultimate goal is to identify key gene-regulatory nodes that can be exploited therapeutically.
In addition to cancer cell-intrinsic mechanisms, it is clear that the tumour microenvironment plays a critical role in regulating cancer progression. There is extensive cross-talk between cancer cells and normal cells within the tumour such as immune cells, fibroblasts and fat cells (adipocytes). The importance of the tumour microenvironment is particularly evident from the strong link between obesity and cancer development and progression. In the Siersbaek group, we are particularly interested in understanding the obesity-driven mechanisms controlling breast cancer biology, including treatment responses and metastasis. To this end, we use single-cell approaches in tumour samples from patients to understand how signals from the normal cells in the tumour microenvironment are rewired in obesity to promote breast cancer progression.
We are always interested in hearing from motivated students and postdocs. Please contact us at siersbaek@bmb.sdu.dk.