Logo des Deutschen Krebsforschungszentrums

CCU Molecular Hematology/Oncology - Basic Research

Chromosomal instability (CIN), a central feature of human malignancies, contributes to genetic heterogeneity, clonal evolution and ultimately to metastasis. Accordingly, our group has a long-standing interest in exploring the molecular mechanisms underlying CIN and untangling its role in the metastatic process and the development of CUP as well as metastatic cancer in general.

Centrosomal aberrations, CIN and metastasis

Chromosomal instability (CIN) describes a form of genome instability characterized by high rates of gains and losses of whole chromosomes (numerical CIN) or large chromosome fragments (structural CIN). It is found in over 90% of solid tumors and in blood cancers. Regarding the mechanisms leading to CIN, we are especially interested in the regulation of mitosis and its disturbance in the context of tumorigenesis. 

Since centrosomal aberrations have been shown to lead to mitotic aberrations and chromosomal instability, a long-standing focus of our group is centrosome biology and its interconnection to malignant transformation and metastasis. Centrosomes are the major microtubule-organizing centers in mammalian cells and organize the bipolar spindle that partitions chromosomes during mitosis. In normal cells, the centrosomes consist of a pair of centrioles embedded in pericentriolar material.

We have recently generated and in-depth characterized transgenic mice that overexpress the centriole replication protein STIL, in order to gain insights into the role of supernumerary centrosomes in CIN induction and subsequent tumor formation in vivo.

 

Extra centrosomes induced by STIL overexpression in transgenic mice cause chromosome missegregation and aneuploidy. Shown here is a multiplex fluorescence in situ hybridization (M-FISH) metaphase of a mouse embryonic fibroblast derived from CMV-STIL+/+ mice.

Moussa AT, Cosenza MR, Wohlfromm T, Brobeil K, Hill A, Patrizi A, Müller-Decker K, Holland-Letz T, Jauch A, Kraft B, Krämer A: STIL overexpression shortens lifespan and reduces tumor formation in mice. PLOS Genetics, 20(10): e1011460, 2024.

To map the landscape of centrosome aberrations in primary tumor tissues at high resolution, we employ correlative light and electron microscopy (CLEM), focused ion beam scanning electron microscopy (FIB/SEM) and EM tomography with subsequent 3D reconstruction and quantitative analysis. Using these approaches we were able to demonstrate for the first time at nanoscale resolution that centriole over-elongation and the subsequent formation of gross structural centrosome aberrations frequently occur in primary human cells and seem to be associated with cell aging.

 

Segmented electron tomography image showing an over-elongated centriole (orange) with additional structural abnormalities in a plasma cell from human bone marrow.

Köhrer S, Dittrich T, Schorb M, Weinhold N, Haberbosch I, Börmel M, Pajor G, Goldschmidt H, Müller-Tidow C, Raab MS, John L, Seckinger A, Brobeil A, Dreger P, Tornóczky T, Pajor L, Hegenbart U, Schönland SO, Schwab Y, Krämer A: High-throughput electron tomography identifies centriole over-elongation as an early event in plasma cell disorders. Leukemia 37: 2468-2478, 2023. / Dittrich T, Köhrer S, Schorb M, Haberbosch I, Börmel M, Goldschmidt H, Müller-Tidow C, Raab MS, Hegenbart U, Schönland SO, Schwab Y, Krämer A: A high-throughput electron tomography workflow reveals over-elongated centrioles in relapsed-refractory multiple myeloma. Cell Reports Methods 2: 100322, 2022.

Project members

5 Employees

  • Dr. Bianca Kraft

    Postdoc, PhD, Deputy

    Contact form: Message to Dr. Bianca Kraft

    Form data is loaded ...

  • Huining Dong

    MD student

    Contact form: Message to Huining Dong

    Form data is loaded ...

  • Katharina Brobeil

    Technician

    Contact form: Message to Katharina Brobeil

    Form data is loaded ...

  • Michael Kirsch

    Technician

    Contact form: Message to Michael Kirsch

    Form data is loaded ...

  • Judith Müller

    Technician

    Contact form: Message to Judith Müller

    Form data is loaded ...

Publications (selected)

2024 - PLOS Genetics 20(10): e1011460.

STIL overexpression shortens lifespan and reduces tumor formation in mice.

Moussa AT, Cosenza MR, Wohlfromm T, Brobeil K, Hill A, Patrizi A, Müller-Decker K, Holland-Letz T, Jauch A, Kraft B, Krämer A

2024 - Nature Genetics 56(12): 2790-2803.

Single-cell analysis reveals dynamic clonal evolution and targetable phenotypes in complex karyotype AML.

Leppä AM, Grimes K, Jeong H, Huang FY, Delgado AA, Boch T, Waclawiczek A, Jauch A, Renders S, Müller-Tidow C, Karpova D, Sohn M, Grünschläger F, Hasenfeld P, Garagorri EB, Thiel V, Dolnik A, Rodriguez-Martin B, Bullinger L, Mrózek K, Eisfeld AK, Krämer A, Sanders AD, Korbel JO, Trumpp A

2023 - Leukemia 37(12): 2468-2478.

High-throughput electron tomography identifies centriole over-elongation as an early event in plasma cell disorders.

Köhrer S, Dittrich T, Schorb M, Weinhold N, Haberbosch I, Bormel M, Pajor G, Goldschmidt H, Müller-Tidow C, Raab MS, John L, Seckinger A, Brobeil A, Dreger P, Tornoczky T, Pajor L, Hegenbart U, Schönland S, Schwab Y, Krämer A

2023 - STAR Protocols 4(3): 102373.

Protocol for high-throughput electron tomography exemplified on centrioles in primary human plasma cells.

Köhrer S, Dittrich T, Schorb M, Haberbosch I, Schwab Y, Krämer A

2022 - Cell Reports Methods 2: 100322.

A high-throughput electron tomography workflow reveals over-elongated centrioles in relapsed-refractory multiple myeloma.

Dittrich T, Köhrer S, Schorb M, Haberbosch I, Börmel M, Goldschmidt H, Müller-Tidow C, Raab MS, Hegenbart U, Schönland SO, Schwab Y, Krämer A

2022 - Cell Death Discovery 8: 484.

Human SLFN5 and its Xenopus Laevis Ortholog Regulate Entry into Mitosis and Oocyte Meiotic Resumption.

Vit G, Hirth A, Neugebauer N, Kraft B, Sigismondo G, Cazzola A, Tessmer C, Duro J, Krijgsveld J, Hofmann I, Berger M, Klüter H, Niehrs C, Nilsson J, Krämer A

2019 - Leukemia 33: 2619–2627.

TP53 deficiency permits chromosome abnormalities and karyotype heterogeneity in acute myeloid leukemia.

Cazzola A, Schlegel C, Jansen I, Bochtler T, Jauch A, Krämer A

2019 - Leukemia 33: 795–799.

SMC3 protein levels impact on karyotype and outcome in acute myeloid leukemia.

Kraft B, Lombard J, Kirsch M, Wuchter P, Bugert P, Hielscher T, et al.

2019 - Genes Chromosomes and Cancer 58: 392–395.

Micronucleus formation in human cancer cells is biased by chromosome size.

Bochtler T, Kartal-Kaess M, Granzow M, Hielscher T, Cosenza MR, Herold-Mende C, et al.

2018 - Blood Advances 2: 2607–2618.

Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma.

Bochtler T, Merz M, Hielscher T, Granzow M, Hoffmann K, Krämer A, et al.

2017 - Cell Reports 20: 1906–1920.

Asymmetric Centriole Numbers at Spindle Poles Cause Chromosome Missegregation in Cancer.

Cosenza MR, Cazzola A, Rossberg A, Schieber NL, Konotop G, Bausch E, et al.

2017 - Blood 129: 1333–1342.

Marker chromosomes can arise from chromothripsis and predict adverse prognosis in acute myeloid leukemia.

Bochtler T, Granzow M, Stölzel F, Kunz C, Mohr B, Kartal-Kaess M, et al.

2016 - Cancer Research 76: 6690–6700.

Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization.

Konotop G, Bausch E, Nagai T, Turchinovich A, Becker N, Benner A, et al.

2016 - Blood Cancer Journal 6, e386.

Karyotype complexity and prognosis in acute myeloid leukemia.

Stölzel F, Mohr B, Kramer M, Oelschlägel U, Bochtler T, Berdel WE, et al.

2015 - Cancer Research 75: 777–778.

Cep63 recruits cdk1 to the centrosome-letter.

Alsara M, Löffler H, Fechter A, Bartek J, Krämer A

2015 - Leukemia 29: 1243–1252.

Role of chromosomal aberrations in clonal diversity and progression of acute myeloid leukemia.

Bochtler T, Fröhling S, Krämer A

2013 - Journal of Clinical Oncology 31: 3898–3905.

Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia.

Bochtler T, Stölzel F, Heilig CE, Kunz C, Mohr B, Jauch A, et al.

2013 - Developmental Cell 25: 229–240.

EGF-induced centrosome separation promotes mitotic progression and cell survival.

Mardin BR, Isokane M, Cosenza MR, Krämer A, Ellenberg J, Fry AM, Schiebel E

2013 - Oncogene 32: 2963–2972.

DNA damage-induced centrosome amplification occurs via excessive formation of centriolar satellites.

Löffler H, Fechter A, Liu FY, Poppelreuther S, Krämer A

2012 - Journal of Cell Science 125: 1353–1362.

STIL is required for centriole duplication in human cells.

Vulprecht J, David A, Tibelius A, Castiel A, Konotop G, Liu FY, et al.

2012 - Cancer Research 72: 5374–5385.

GF-15, a novel inhibitor of centrosomal clustering, suppresses tumor cell growth in vitro and in vivo.

Raab MS, Breitkreutz I, Anderhub S, Rønnest MH, Leber B, Larsen TO, et al.

2010 - Nature Medicine 16: 198–204.

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease.

Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, et al.

2010 - Science Translational Medicine 2: 33ra38.

Proteins required for centrosome clustering in cancer cells.

Leber B, Maier B, Fuchs F, Chi J, Riffel P, Anderhub S, et al.

2009 - Journal of Cell Biology 185: 1149–1157.

Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1.

Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1.

2007 - Cancer Research 67: 6342–6350.

Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen.

Rebacz B, Larsen TO, Clausen MH, Rønnest MH, Löffler H, Ho AD, Krämer A

2005 - Nature 434: 864–870.

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.

Bartkova J, Horejsí Z, Koed K, Krämer A, Tort F, Zieger K, et al.

2004 - Nature Cell Biology 6: 884–891.

Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase.

Krämer A, Mailand N, Lukas C, Syljuåsen RG, Wilkinson C, Nigg EA, et al.

2003 - Blood 101: 289–291.

Centrosome aberrations in acute myeloid leukemia are correlated with cytogenetic risk profile.

Neben K, Giesecke C, Schweizer S, Ho AD, Krämer A