Konsequenzen überzähliger Zentrosomen in STIL-transgenen Mäusen
Zusammenfassung der Projektergebnisse
Chromosomal instability (CIN) is a hallmark of cancer. It increases the probability of oncogenic events and creates a heterogeneous cell population with enhanced abilities to adapt and evolve. CIN results from errors in chromosome segregation during mitosis. Mechanistically, the most prominent cause of chromosome missegregation are supernumerary centrosomes. Centrosomes are the major microtubule-organizing centers in mammalian cells and consist of a pair of centrioles embedded in pericentriolar material. They duplicate in S phase, with the formation of one daughter centriole next to each preexisting mother. During mitosis, the two newly formed centrosomes of a cell migrate to opposite poles, contributing to bipolar spindle formation. To ensure accurate chromosome segregation, centriole numbers are tightly controlled in non-transformed cells. Abnormalities in centrosome structure and number have been found in various malignancies, are associated with CIN and poor prognosis, and represent an early event in the evolution of malignant phenotypes. However, data on the tumorigenic potential of supernumerary centrosomes generated by overexpression of PLK4 in mice are conflicting. To circumvent extra-centrosomal effects of PLK4 kinase and to generate PLK4-independent evidence, we created genetic mouse models to assess the impact of centrosome amplification induced by overexpression of the structural centriole protein STIL on tumor formation in vivo. Mouse embryonic fibroblasts (MEFs) derived from STIL-overexpressing mouse embryos displayed high levels of STIL protein and supernumerary centrosomes, leading to the induction of chromosome aberrations and micronuclei in vitro. Similar to the induction of supernumerary centrosomes by overexpression of PLK4 or cytokinesis failure, STIL overexpression elicited a growth disadvantage to MEFs in tissue culture and led to increased rates of still births in vivo. Unexpectedly however, STIL-induced centrosome amplification reduced spontaneous tumor formation in vivo. Likewise, STIL-induced centrosome amplification significantly reduced the frequency of carcinogen-induced skin tumors in a standardized skin tumorigenesis assay. Together, our data suggest that similar to aneuploidy itself, supernumerary centrioles seem to act both oncogenically and as a tumor suppressor, depending the levels of STIL transgene-induced centrosome amplification. In line, whereas mouse models with low level overexpression of PLK4 seem to display increased rates of tumor formation, higher PLK4 levels had no impact on tumorigenesis.
Projektbezogene Publikationen (Auswahl)
- Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues [Invited review; Special issue on Centrosomes and Chromosome Stability]. Chromosome Res 24: 105-126, 2016
Cosenza MR, Krämer A
(Siehe online unter https://doi.org/10.1007/s10577-015-9505-5) - Pharmacological inhibition of centrosome clustering by slingshotmediated cofilin activation and actin cortex destabilization. Cancer Res 76: 6690-6700, 2016
Konotop G, Bausch E, Nagai T, Turchinovich A, Becker N, Benner A, Boutros M, Mizuno K, Krämer A, Raab MS
(Siehe online unter https://doi.org/10.1158/0008-5472.CAN-16-1144) - Asymmetric Centriole Numbers at Spindle Poles Cause Chromosome Instability in Cancer. Cell Rep 20: 1906-1920, 2017
Cosenza MR, Cazzola A, Rossberg A, Schieber NL, Konotop G, Bausch E, Slynko A, Holland-Letz T, Raab MS, Dubash T, Glimm H, Poppelreuther S, Herold-Mende C, Schwab Y, Krämer A
(Siehe online unter https://doi.org/10.1016/j.celrep.2017.08.005) - SMC3 protein levels impact on karyotype and outcome in acute myeloid leukemia. Leukemia 33: 795- 799, 2019
Kraft B, Lombard J, Kirsch M, Wuchter P, Bugert P, Hielscher T, Blank N, Krämer A
(Siehe online unter https://doi.org/10.1038/s41375-018-0287-6) - TP53 deficiency permits chromosome abnormalities and karyotype heterogeneity in acute myeloid leukemia. Leukemia 33: 2619-2627, 2019
Cazzola A, Schlegel C, Jansen I, Bochtler T, Jauch A, Krämer A
(Siehe online unter https://doi.org/10.1038/s41375-019-0550-5)
