The goal of our studies is to understand the mechanisms responsible for maintenance of genomic stability in mammalian cells. The underlying pathways include the major tumor suppressors, and these pathways are obvious candidates for cancer therapeutic targeting.
We focus on three connected research themes:
Novel factors underlying familial breast cancer (FBC)
Pathways promoting genome maintenance are very frequently altered in FBC, because they are disabled by dominant variants often driving early-onset tumorigenesis. Importantly, it is estimated that 70 % of causal familial cancer variants remain to be identified. Thus, major unresolved aspects await elucidation, which is crucial as the identification of cancer inherent defects provides potential for therapeutically targeting cancer specific pathways.We use a combination of screening methodologies to uncover major FBC factors including next generation sequencing of blood from suspected carrier families. These new factors -including the cancer associated variants- are thoroughly investigated to understand their molecular function thereby uncovering potential roles in cancer development and treatment.
Figure 1. Novel factors underlying familial breast cancer (FBC). In a collaboration with clinicians from Copenhagen General Hospital we identify and characterize new familial breast cancer genes based on blood sample sequencing.
New genome maintenance factors
We unravel pathways that suppress genome instability even in the absence of exogenous DNA damage. We use a combination of screening methodologies to identify these factors followed by functional and molecular investigations to unravel roles in cancer development and treatment.
Figure 2. New genome maintenance factors: The Histone Methyltransferase SETD8 protects the genome. This is evidenced by accummulating genotoxic stress markers following SETD8 removal (monitored by gamma-H2AX and Rad51 foci). We unravel function and mechanisms of the SETD8 pathway as well as selected major genome maintenance pathways.
The cellular response to ionizing radiation
Radiation is a DNA damaging approach that together with surgery constitute the major curative breast cancer treatment modality. Specifically, we are unravelling new DNA damage response pathways with the ultimate goal to sensitize p53-deficient cancer cells to radiation. Furthermore, we are generating inhibitors to the new factors which we expect can serve as proof-of-concept radiosensitizing agents.
Movie1: The cellular response to ionizing radiation. Time lapse movie displays checkpoint control after irradiation (left movie). Removal of the BRCA2 tumor suppressor leads to checkpoint override (right movie). We identified this new function of BRCA2 in radiation response through genetic screening.
Galanos P, Vougas K, Walter D, Polyzos A, Maya-Mendoza A, Haagensen EJ, Kokkalis A, Roumelioti FM, et al. (2016) Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nature Cell Biology PMID: 27323328
Nielsen FC, Hansen TvO, Sørensen CS. (2016) Hereditary Breast and Ovarian Cancer: New Genes in Confined Pathways. Nature Reviews Cancer, in press
Ahlskog J, Larsen BD, Kavya A, Sørensen CS. (2016) ATM/ATR‐mediated phosphorylation of PALB2 promotes RAD51 function. EMBO Reports. PMID: 27113759
Walter D, Hoffmann S, Komseli ES, Rappsilber J, Gorgoulis V, Sørensen CS. (2016) SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication. Nature Communications. PMID: 26818844
Boyer AS, Walter D, Sørensen CS. (2016) DNA replication and cancer: From dysfunctional replication origin activities to therapeutic opportunities. Seminars in Cancer Biology, Pp 1044-57. PMID: 26805514
Shoaib M & Sørensen CS. (2015) Epigenetic Deficiencies and Replicative Stress: Driving Cancer Cells to an Early Grave. Cancer Cell, PMID: 265551681.
Dobbelstein, M & Sørensen, CS. (2015) Exploiting replicative stress to treat cancer. Nature Reviews Drug Discovery, PMID: 25953507.
Fugger K, Mistrik M, Neelsen KJ, Yao Q, Zellweger R, Kousholt AN, Haahr P, Chu WK, Bartek J, Lopes M, Hickson ID, Sørensen CS. (2015) FBH1 Catalyzes Regression of Stalled Replication Forks. Cell Reports, PMID: 25772361.
Klein DK, Hoffmann S, Ahlskog JK, O'Hanlon K, Quaas M, Larsen BD, Rolland B, Rösner HI, Walter D, Kousholt AN, Menzel T, Lees M, Johansen JV, Rappsilber J, Engeland K, Sørensen CS. (2015) Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control. Nature Communications, PMID: 25557911.
Klein DK, Hoffmann S, Ahlskog JK, O’Hanlon K, Quaas M. Larsen BD, Rolland B, Rösner HI, Walter D, Kousholt AN, Menzel T, Lees M, Johansen JV, Rappsilber J, Engeland K, Sørensen CS (2014). Nature Communications.
Members of Sørensen group