OncologyGenomic Instability and Cancer Laboratory

Genomic Instability and Cancer Laboratory

The recognition of many types of DNA lesions activates the cellular DNA damage response (DDR). The DDR orchestrates the appropriate cellular programs to maintain genome integrity after genotoxic stress. Indices of an activated DDR are evident in many pre-cancerous and cancerous lesions and it has been proposed to act as an inducible barrier to malignancy. This proposition is supported by both animal models and human genetic instability disorders that are caused by mutations in proteins that control the DDR. Understanding the signal transduction networks governed by the DDR, and the consequences of their impairment, will facilitate our understanding of tumor development and enhance cancer treatment methods.

Studies in our lab will focus on the role of the DDR in tumor suppression. Rare human diseases, including Ataxia-telangiectasia and Nijmegen Breakage Syndrome, lead to developmental disorders and tumor predisposition due to mutations in genes involved in the DDR. Using patient samples and murine models of the human diseases, we will analyze the molecular signaling that controls various components of the DDR and determine their role in tumor suppression.

1.The role of the Mre11 complex in tumor suppression.
Genetic studies in mice suggest that the G2/M checkpoint, which prevents cells with DNA damage from entering mitosis, is important for maintaining genome stability and suppressing cancer. We will further analyze the role of the Mre11 complex (Mre11, Rad50, Nbs1) in this checkpoint response, identify the cellular requirements to initiate and maintain the checkpoint, and determine its role in preventing malignancy.

2. The regulation of apoptosis by the Chk2 kinase.
The checkpoint kinase Chk2 plays a key role in triggering apoptosis in response to ionizing radiation and mice lacking Chk2 are resistant to radiation toxicity. We have observed that loss of Chk2 in mice with hypomorphic Mre11 complex mutations leads to a broad spectrum of tumors. To understand the role of Chk2 in tumor suppression we are analyzing its regulation by other members of the DDR and taking numerous approaches to identify relevant targets of its kinase activity.

Figure legend: A. Nbs1, a component of the Mre11 complex, localizes to the nucleus (top panel) and accumulates in foci at sites of damage following ionizing radiation (IR) treatment (bottom panel). B. Radiation induced chromosomal instability in mouse (top) or human (bottom) cells with mutations in the Mre11 complex. Chromatid breaks are indicated by red arrows. C. Tumors from mice with mutations in the Mre11 complex and Chk2. H&E stained sections of a high grade angiosarcoma (left) and a high grade osteogenic sarcoma (right) at 400X. Images courtesy of Sam Singer.

3. The influence of the damage response on chromatin composition.
The modulation of chromatin composition and the remodeling of DNA ends by the Mre11 complex and other DDR proteins is important for DNA repair as well as initiating the appropriate cellular responses. We will elucidate the signaling pathways that connect recognition of DNA lesions with essential changes in chromatin composition.

Terré B, Piergiovanni G, Segura-Bayona S, Gil-Gómez G, Youssef SA, Attolini CS, Wilsch-Bräuninger M, Jung C, Rojas AM, Marjanović M, Knobel PA, Palenzuela L, López-Rovira T, Forrow S, Huttner WB, Valverde MA, de Bruin A, Costanzo V and Stracker TH.
Embo J, 35 (9), 942-60 (2016)
Pereira-Lopes S, Tur J, Calatayud-Subias JA, Lloberas J, Stracker TH and Celada A.
Blood, (2015)
Rein K, Yanez DA, Terré B, Palenzuela L, Aivio S, Wei K, Edelmann W, Stark JM and Stracker TH.
Nucleic Acids Res, 43 (15), 7371-87 (2015)
Marjanović M, Sánchez-Huertas C, Terré B, Gómez R, Scheel JF, Pacheco S, Knobel PA, Martínez-Marchal A, Aivio S, Palenzuela L, Wolfrum U, McKinnon PJ, Suja JA, Roig I, Costanzo V, Lüders J and Stracker TH.
Nat Commun, 6 7676 (2015)
Arroyo R, Suñé G, Zanzoni A, Duran-Frigola M, Alcalde V, Stracker TH, Soler-López M and Aloy P.
J Mol Biol, 427 (6 Pt B), 1436-50 (2015)
Chen WT, Ebelt ND, Stracker TH, Xhemalce B, Van Den Berg CL and Miller KM.
Elife, 4 (2015)
Zhen Y, Knobel PA, Stracker TH and Reverter D.
J Biol Chem, 289 (50), 34838-50 (2014)
Rein K and Stracker TH.
Exp Cell Res, 329 (1), 162-9 (2014)
Torres AG, Piñeyro D, Filonava L, Stracker TH, Batlle E and Ribas de Pouplana L.
Febs Lett, 588 (23), 4279-86 (2014)
Knobel PA, Belotserkovskaya R, Galanty Y, Schmidt CK, Jackson SP and Stracker TH.
Mol Cell Biol, 34 (11), 2062-74 (2014)
Bianchi J, Rudd SG, Jozwiakowski SK, Bailey LJ, Soura V, Taylor E, Stevanovic I, Green AJ, Stracker TH, Lindsay HD and Doherty AJ.
Mol Cell, 52 (4), 566-73 (2013)
Stracker TH, Roig I, Knobel PA and Marjanović M.
Front Genet, 4 37 (2013)
Foster SS, De S, Johnson LK, Petrini JH and Stracker TH.
P Natl Acad Sci Usa, 109 (25), 9953-8 (2012)

This group is financially supported by the following:

  • Ministerio de Economía y Competitividad (MINECO)
  • European Commission (EC), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa"

     

Group news & mentions

<p>Cross sections of wild type or TLK2 deficient embryos stained for the proliferative marker Ki67. Embryos lacking TLK2 (left) appear morphologically normal but developmentally delayed. (S. Segura-Bayona, IRB Barcelona)</p>
18 Jul 2017

Several media have echoed research by IRB Barcelona researcher Travis H. Stracker on the key role of the TLK2 gene for the development of the placenta and for embryo viability in mice.

<p>Cross sections of wild type or TLK2 deficient embryos stained for the proliferative marker Ki67. Embryos lacking TLK2 (left) appear morphologically normal but developmentally delayed. (S. Segura-Bayona, IRB Barcelona)</p>
17 Jul 2017

The placenta, a transient organ that links the developing embryo to its mother, is responsible for nutrient, waste and gas exchange between the foetus and the mother.

<p>This graphic image simulates the metabolic fluxes in cells, with the nutrients marked with a stable isotope that allow to study the fluxes and the transformation dynamics of these nutrients.</p>
23 Feb 2017

A study published this week in the journal Angewandte Chemie presents a new methodology that uses Nuclear Magnetic Resonance (NMR) to study cell metabolism.

Upcoming events

13 Sep
Aula Fèlix Serratosa, Parc Científic de Barcelona
Speaker:
Speaker: Sebastian Pons, PhD, Principal Investigator, Neural Proliferation Control LAB, IBMB-CSIC
20 Sep
Aula Fèlix Serratosa, Parc Científic de Barcelona
Speaker:
Speaker: Isabel Almudi, Ph.D. Developmental Biology, Evolutionary Biology Andalusian Center for Developmental Biology, Sevilla, Spain.
27 Sep
Aula Fèlix Serratosa, Parc Científic de Barcelona
Speaker:
Speaker: Cristina Pujades, Ph.D. Group Leader of the Department of Experimental and Health Sciences, University Pompeu Fabra, PRBB, Barcelona, Spain.