Institut für Tierpathologie

Therapy Escape of Cancer

Prof. Dr. Sven Rottenberg, Direktor
Prof. Dr. Sven Rottenberg, Direktor

Cancer Therapy Resistance

Patients with tumors that are defective in DNA repair by homologous recombination (HR) are often sensitive to DNA-repair targeting agents. However, despite initial responses to cancer therapy, resistance of primary or disseminated tumors eventually emerges, which minimizes therapeutic options and greatly reduces survival. The molecular mechanisms underlying this therapy escape are mostly unclear.

In my group we are studying the basic mechanisms of therapy escape by using distinguished mouse models for BRCA1- or BRCA2-deficient breast cancer, which closely mimic the disease found in humans. Due to the BRCA inactivation, the tumors that arise lack HR-directed DNA repair; an Achilles heel that has provided a therapeutic opportunity to eradicate tumors with DNA damage-causing agents. However, similar to the situation in cancer patients, we observe that cancer cells in these models can escape the deadly effects of classical chemotherapy, novel targeted drugs or radiotherapy. Thus, these resistance models that we have established provide a unique opportunity to explore therapy escape mechanisms

Mitarbeitende

Gruppenleiter

Mitarbeitende

Publikationen

5 ausgewählte Publikationen

  • H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours. Dibitetto, Liptay et al. Nature Communications 15:4430, 2024.

    In this article we demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumors and establish a function of H2AX separable from its classical role in DNA damage signaling and DSB repair.

  • Functional radiogenetic profiling implicates ERCC6L2 in non-homologous end joining. Francica, Mutlu et al. Cell Reports 32:108068, 2020.
    In this study we functionally dissected genes that are dispensable for the normal growth of cells but become essential for cell fitness following IR exposure. With ERCC6L2 we identified a novel player that contributes to NHEJ.

  • Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Gogola et al. Cancer Cell 33: 1078-1093, 2018.
    This article shows that PARG depletion is a way for cancer cells to escape the deadly effects of PARP inhibition without restoring homology-directed DNA repair.
     
  • BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance. Duarte, Gogola et al. Nature Methods 15:134-140.
    Here we describe the development of three-dimensional cancer organoids derived from BRCA1- and BRCA2-deficient mouse mammary tumors. These can be easily genetically modified, making them a powerful tool for genetic studies of tumor biology and drug resistance.
     
  • REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Xu et al. Nature 521:541-4, 2015.
    This article describes a BRCA1-independent mechanism of homology-directed DNA repair restoration that causes PARPi resistance and provides novel insights into basic DNA repair mechanisms.

 

For a complete overview of the publications of the Rottenberg laboratory please see at ncbi.

über Sven Rottenberg

CURRENT POSITION

  • 2019 –    Vice Dean, Vetsuisse Faculty, University of Bern, Switzerland
  • 2017 –   Chair, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern
  • 2014 –   Director of the Institute of Animal Pathology, Vetsuisse Faculty, University of Bern

EDUCATION

  • 2004 Diploma of the European College of Veterinary Pathologists (ECVP)
  • 2003 PhD, Vetsuisse Faculty of the Universities Bern and Zürich, Switzerland
  • 2000 Doctor of Veterinary Medicine (DVM), University of Bern, Switzerland
  • 1997 Diploma (“Staatsexamen”) in Veterinary Medicine, Faculty of Veterinary Medicine, Free University of Berlin, Germany

PROFESSIONAL AND ACADEMIC EXPERIENCE

  • 2012 – 2014 Group leader (associate professor level), Molecular Oncology, The Netherlands Cancer Institute, Amsterdam
  • 2010 – 2012 Associate staff scientist, Molecular Biology, The Netherlands Cancer Institute, Amsterdam
  • 2007 – 2010 Senior postdoctoral fellow, Molecular Biology, The Netherlands Cancer Institute, Amsterdam
  • 2004 – 2007 Postdoctoral fellow, Molecular Biology, The Netherlands Cancer Institute, Amsterdam
  • 1999 – 2004 Resident in the combined Anatomic Veterinary Pathology/PhD program, Institute of Animal Pathology, University of Bern, Switzerland
  • 1998 – 1999 Resident in Domestic Animal Sciences, University of Kiel, Germany

INSTITUTIONAL RESPONSIBILITIES

  • 2019 –   Steering Committee Member, Experimental Animal Center, University of Bern
  • 2016 –   Faculty board of the Vetsuisse Faculty, University of Bern
  • 2015 –   Chair, Comparative pathology platform (COMPATH) of the University of Bern
  • 2014 –   Steering Committee Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern
  • 2014 –   Chair, Institute of Animal Pathology, Vetsuisse Faculty, University of Bern

MEMBERSHIPS IN SCIENTIFIC PANELS

  • 2020 –   SNSF PRIMA Evaluation Commission Life Sciences, Switzerland
  • 2017 –   Board member of the Hans Sigrist Foundation, University of Bern
  • 2015 –   Expert committee “Molecular Biology & Biochemistry” of the Graduate School for Cellular and Biomedical Sciences, University of Bern
  • 2015 –   Working group “Non-human biobanks” (part of Swiss Biobanking Platform)
  • 2014 –   Clean Mouse Facility Kuratorium, University of Bern
  • 2007 –  2013 Exam Committee of the European College of Veterinary Pathologists (ECVP)

RESEARCH PROJECTS AS LEADING INVESTIGATOR

  • 2021 – 2026  European Research Council (ERC) Advanced grant (883877): Targeting the essentialome of radiotherapy-resistant cancer (TETHER); EUR 2,500,000
  • 2021 – 2025  SNSF Sinergia grant (CRSII5_198543, co-PIs Vassily Hatzimanikatis, Volker Heussler, Deborah Stroka): Functional chemoinformatic modelling of the host cell metabolome to fight apicomplexan parasites; CHF 3,133,006
  • 2019 – 2023  SNSF grant (310030_189127): Identifying the essentialome of Theileria-induced host cell transformation; CHF 374,009
  • 2019 – 2021  Wilhelm Sander-Stiftung: Cancer therapy resistance: alterations in the DNA repair as underlying mechanism; EUR 177,000
  • 2018 – 2022 Swiss Cancer League (KLS-4282-08-2017) Understanding the role of the CST complex in the synthetic lethal interaction between BRCA1 deficiency and PARP inhibition; CHF 330,000
  • 2016 – 2021 European Research Council (ERC) consolidator grant (681572): Synthetic viability of homologous recombination-deficient cancers (SYNVIA); EUR 2,000,000

SUPERVISED PHD THESES (AS MAIN SUPERVISOR)

  • Ongoing: Christina Andronikou, Morgane Decollogny, Carmen Disler, Marine Inglebert, Martín González Fernández, Taina Kaiponen, Lea Lingg, Martin Liptay, Cédric Walker
  • 2020 Merve Mutlu: Functional genetic profiling to identify genes that influence radiotherapy response
  • 2019: Ewa Gogola: Resistance to PARP inhibition by DNA damage response alterations in BRCA1/2-deficient tumors
  • 2018 Nora Gerhards: Exploring mechanisms of anti-cancer therapy response using haploid insertional mutagenesis screens
  • 2018 Sandra Huber (co-supervision with Kerry Woods): Protein interactions at the host-parasite interface in Theileria annulata-infected leukocytes
  • 2018 Sohvi Blatter: Targeting drug tolerance of residual Brca1-mutated mouse mammary tumors
  • 2016 Guotai Xu: Loss-of-function shRNA screens to identify mechanisms of PARP inhibitor resistance in BRCA1-mutated mouse mammary tumors
  • 2013 Janneke E Jaspers (co-supervision with Jos Jonkers): Targeting anti-cancer drug resistance mouse models of breast cancer
  • 2013 Serge AL Zander: Resistance to topoisomerase inhibitors in BRCA1-deficient mouse mammary tumors

SUPPORT OF RESEARCH FELLOWSHIPS OF YOUNG SCIENTISTS

  • 2014 –   Christina Andronikou (SNSF Doc Mobility, 2020), Joana Santos Barbosa (Marie Skłodowska-Curie Action-Individual Fellowship, 2017-2019), Sohvi Blatter (SNSF MD-PhD program, 2014-2017), Martina Dettwiler (SNSF Doc Mobility, 2016), Natalia Domanitskaia (Marie Skłodowska-Curie Action-Training Network, 2015-2017), Paola Francica (Bernese Cancer League 2019 and Stiftung für Klinisch-Experimentelle Tumorforschung 2021-2023), Nora Gerhards (SNSF Doc Mobility, 2015), Kerstin Hahn (SNSF Early Postdoc Mobility, 2018-2020), Martin Liptay (Boehringer Foundation, 2017-2019), Philipp Olias (SNSF Ambizione, 2017-2021), Kerry Woods (SNSF Ambizione, 2014-2018)

PRIZES, AWARDS

  • 2019  Pilot Project Award, Bern Center for Precision Medicine, Switzerland (CHF 54,000)
  • 2011  VIDI Award of the Netherlands Organization for Scientific Research to study mechanism of chemotherapy resistance (EUR 800,000)
  • 2010  American Association for Cancer Research (AACR) – Translational Cancer Medicine Award
  • 2010  Best Poster Award, Annual Meeting on Cancer and Control of Genomic Integrity, Stockholm, Sweden
  • 2005 – 2007 Fellowship by the Swiss Foundation for Medical-Biological Grants (SSMBS, PASM33-108943) for the continuation of the study of multidrug resistance in Prof. Piet Borst’s group at the Netherlands Cancer Institute in Amsterdam)
  • 2004 – 2005 Fellowship by the Swiss National Science Foundation (PBBEB-104429) for the study of multidrug resistance in Prof. Piet Borst’s group at the Netherlands Cancer Institute in Amsterdam
  • 2003  Young Investigator Award of the American Society of Veterinary Pathologists (ASVP)
  • 2003  Swiss Society of Tropical Medicine and Parasitology Award 2003

(CO-) ORGANISATION OF CONFERENCES

  • 2021 EMBO workshop on "The DNA-damage response in cell physiology and disease" in Sounio, Greece
  • 2019 EuroPOLA 2019 (Laboratory Animal Pathology), University of Bern
  • 2017 EuroPOLA 2017 (Laboratory Animal Pathology), University of Bern
  • 2014 Preclinical Assays in Cancer Therapy, Curie Institute, Paris, France
  • 2012 Preclinical Assays in Cancer Therapy, Netherlands Cancer Institute, Amsterdam