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Gargiulo Lab

Molecular Oncology

Profile

Cancer arises in normal cells by means of genetic and epigenetic alterations. Our research focuses on understanding the molecular mechanisms regulating tumor homeostasis and response to anti-cancer therapy.

In other words, we want to understand how tumor tissues balance self-growth and interactions with the host. Both processes can ensure cancer survival and govern critical cell decisions such as to whether self-renew, differentiate or die (i.e. homeostasis). Ultimately, tumor homeostasis can be viewed as the dark side of the normal tissue self-regulation. 

We also want to know how do cancer cells deal with the therapy-induced stress.

Learning about these mechanisms will enable us to identify cancer-specific vulnerabilities, which in turn may pave the way to identifying more effective treatments.

Team

Research

Background

Cancer arises in normal cells by means of genetic and epigenetic alterations. Our research focuses on understanding the molecular mechanisms regulating tumor homeostasis and response to anti-cancer therapy.

In other words, we want to understand how tumor tissues balance self-growth and interactions with the host. Both processes can ensure cancer survival and govern critical cell decisions such as to whether self-renew, differentiate or die (i.e. homeostasis). Ultimately, tumor homeostasis can be viewed as the dark side of the normal tissue self-regulation. 

We also want to know how do cancer cells deal with the therapy-induced stress.

Learning about these mechanisms will enable us to identify cancer-specific vulnerabilities, which in turn may pave the way to identifying more effective treatments.

Approach

One of the approaches we take is to model human cancers in laboratory animals using genetic alterations described in patients (see example in figure below). In turn, these models are used to study:

  • genotype-to-molecular phenotype connections (Fig.1b)
  • molecular mechanisms of tumor growth and response to therapy (Fig.1c)
  • target discovery and validation (Fig.1d)

In the long run, we aim to exploit animal models as “surrogate” or “targeted” patients to ultimately identify novel anti-cancer treatments and biomarkers for response.

Mechanistically, we focus on genetic and epigenetic control of gene expression in cancer cells. We make use of a combination of experimental and computational approaches among which: adult stem cells genetic engineering, in vivo tumor modeling, in vivo genetic screens and genome-wide binding, occupancy & expression profiling by high throughput sequencing. As we thrive to achieve a conceivably rapid translation of our experimental efforts into clinical oncology, we leverage our results against large publicly available repositories containing patients’ molecular and clinical information.

Focus on solid tumors

Currently, we focus our work on solid tumors such as brain and lung cancers. In particular, the lab established a long-term research program dealing with the Glioblastoma Multiforme (GBM). The GBM is the most common primary brain tumor, and is currently incurable. It is urgent to devise treatments best fitting individual patients (precision medicine) and be able to predict the patients’ response to the chosen therapy. Both tumor heterogeneity and resistance to available treatments significantly affect GBM clinical management. As mentioned above, we approach these problems by creating and characterizing “humanized” animal models of GBM accurately reflecting patients at molecular level and exploiting these models in state-of-the-art genetic screens in vivo. In this setting, we aim to identify molecular biomarkers for response to standard-of-care for GBM patients as well as to uncover mechanisms of intrinsic and acquired resistance.

For lung cancer, we are interested in those tumor subtypes driven by the Kras oncogene, for which effective treatments are currently lacking.

Publications

News

Joint Research Programs

Our research includes a Joint Research Program with an Independent Fellow.

As an alternative to non-permanent MDC fellowship positions that have no longer foreseeable openings (e.g. Delbrück & Cecile Vogt fellows), the independent fellowship scheme allows scientifically autonomous scientists to carry out their own research provided that they acquire dedicated external funding. The MDC host research group shares the lab space, infrastructure and scientifically collaborates to the projects that fall within the scope of the host lab.

Dr. Michela Serresi, PhD

Team Leader/BSIO Awardee

Contact: Michela.Serresi@mdc-berlin.de

Education

2000-2003 PhD, Applied Biomolecular Science, “Universita’ Politecnica delle Marche” Ancona, Italy
1992-1997 Master Degree Biological Sciences Universita’ Politecnica delle Marche”, Ancona Italy

Professional experience (selection)

Present appointment: Team Leader, Molecular Oncology, Max Delbruck Center, Berlin Germany – BSIO/Fia Awardee
Oct 2010 to Sept 2016: Postdoctoral fellow, Division of Molecular Genetics, Netherland Cancer Institute, Amsterdam, The Netherlands (NKI).
Jan 2010 to Sept 2010: Team Leader, IIT@CNI NEST- Italian Institute of Technology, Italy
Jan 2006 to Dec 2009: Senior Scientist, Scuola Normale Superiore, Pisa, Italy (Group: Prof. Fabio Beltram)
Sep 2001 to Dec 2005: Visiting scientist and Postdoctoral fellow, Division of Experimental Oncology II, (Group: Prof. Pier Paolo Di Fiore), European Institute of Oncology Milan, Italy

Awards and Grants

  • 2019 DFG grant “Identification of the molecular mechanisms underlying lung cancer metastasis”
  • 2017 Award of the National Scientific Habilitation as Associate Professor (scientific area Molecular Biology 05/E1)
  • 2015 BSIO Female Independency Award 2015-2018, Berlin

  • 2012 Award of the National Scientific Habilitation as Associate Professor (scientific area Applied Biology 05/F1)
  • 2010 Co-Chair at the International Meeting “Biophysical Society 54th Annual Meeting” San Francisco, California (Platform AS “Exocytosis and Endocytosis”) 20-24-02-2010
  • 2006-2008 Principal Investigator of Workpackage II “Drugs, Nanoreporters and Nanoactuators Delivery” Joined Project Scuola Normale Superiore –Italian Institute of Technology
  • 2000-2002 Fellowship from FIRC (Fondazione Italiana Ricerca sul Cancro) “Mario and Valeria Rindi”

Research Field

Metastasis is the most common and severe complication arising in cancer patients. A question in this field that is still very much open, is how a primary cancer cell acquires metastatic traits and what are the molecular events governing this process.

Our research activity is to identify the main drivers of metastasis and clarifying their mechanisms of action. This information would enable:

  1. identifying high-risk patients, and
  2. design patient-tailored therapies.

We study this topic in a mouse model for lung cancer, which is the most common cancer in the western world and death by lung cancer is often caused by metastases.

We are interested in understanding the molecular mechanisms underpinning lung cancer dissemination to distal organs. While next generation sequencing technologies allowed to better understand the genetic basis of cancer, discriminating alterations that are driving the processes of tumor evolution from passenger mutations still remains a major challenge.  Moreover, extensive sequencing efforts of evolving primary and secondary tumors indicate that cancer genomes can be extremely complex and patients’ specific. Genetic screens represent powerful tools for identifying causal genes in various hallmarks of cancer progression. To address this topic, we are exploiting in vivo CRISPR-Cas9 screening strategies with dedicated and validated lung cancer animal models.

Team members

Sonia Kertalli, BSIO phD student

Past members: Jikke Wierikx, Student AVANS University of Applied Sciences, The Netherlands, Marialucia Massaro Erasmus traineeship, Universita’ di Trento, Italy

5 Selected publications

  • Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition
    Serresi M, Kertalli S, Lifei Li, Schmitt MJ, Dramaretska Y , Wierikx J, Hulsman D, Gargiulo G, Science Advances. 2021 in press
  • Phenotypic mapping of pathological crosstalk between glioblastoma and innate immune cells by synthetic genetic tracing.
    Schmitt MJ, Company C, Dramaretska Y, Barozzi I, Göhrig A, Kertalli S, Großmann M, Naumann H, Sanchez-Bailon MP, Hulsman D, Glass R, Squatrito M, Serresi M, Gargiulo G. Cancer Discov. 2020 Dec 23:CD-20-0219. doi: 10.1158/2159-8290.CD-20-0219. 
  • Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities.
    Serresi M, Siteur B, Hulsman D, Company C, Schmitt MJ, Lieftink C, Morris B, Cesaroni M, Proost N, Beijersbergen RL, van Lohuizen M, Gargiulo G. J Exp Med. 2018 Dec 3;215(12):3115-3135. doi: 10.1084/jem.20180801. Epub 2018 Nov 28.
  • Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer.
    Serresi M, Gargiulo G, Proost N, Siteur B, Cesaroni M, Koppens M, Xie H, Sutherland KD, Hulsman D, Citterio E, Orkin S, Berns A, van Lohuizen M. Cancer Cell. 2016 Jan 11;29(1):17-31. doi: 10.1016/j.ccell.2015.12.006. 
  • In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis.
    Gargiulo G, Cesaroni M, Serresi M, de Vries N, Hulsman D, Bruggeman SW, Lancini C, van Lohuizen M. Cancer Cell. 2013 May 13;23(5):660-76. doi: 10.1016/j.ccr.2013.03.030.

Working with us

We are always open to applications from highly motivated, creative individuals with past training aligned with our interests and some degree of independence to enrich and expand our team.

The lab generally advertises open positions on the MDC website and through professional and social networks.

 To account for the corona restrictions and to maximize the productivity of the applications, we are currently open to:

  • Computational early-career scientists at master and graduate student levels. Target profile: any individual with demonstrated programming, scripting, and statistical data analysis in R, Perl/Python and a solid background in machine learning. Education in bioinformatics, computational biology, expertise in single-cell RNA-seq analyses, or machine learning is advantageous. To apply for this position, please contact the group leader with your CV, referees' contact and tailor your application to the specific computational aspects of our past work. We have access to many community-generated datasets. We also have lab-generated WGS and WGBS, RNA- & scRNA-seq, ATAC-seq datasets. For those individuals with a specific interest in method development, we are developing pipelines to integrate multi-omics profiles or to generate synthetic reporters for generic tracing (see publications). A ~150-word synopsis of future interest with some degree of specificity will be advantageous.
  • Experimental early-career scientists at the master student level. Target profile: any individual with demonstrated hands-on experience with genetic engineering of delicate mammalian cells (e.g. embryonic or adult stem cells). To apply for this position, please contact the group leader with your CV, referees' contact, and one slide of data generated in your previous/current focusing on the technical aspect of the experiments. We have options to accommodate students with some degree of independence on ongoing projects. Still, a ~150-word synopsis of future interest with some degree of specificity will be advantageous.
  • Graduate students through either the MDC or the BSIO graduate program. Please feel invited to apply to one of these programs, as there are generally three openings per year. In case you wanted to specifically discuss a request that is not addressed here or on the MDC/BSIO websites, you are welcome to do so. In that case, please directly address the matter of interest.
  • Early career postdoctoral fellows (<1 year from Ph.D. or equivalent degree). We are always open to outstanding applicants. If your profile aligns with the requirements for applying to AvH, EMBO long-term, and Marie Curie fellowships and have academic aspirations or targeted technological interests, you are welcome to apply to the group leader directly even without an open position. In this case, please mind the application deadline for the postdoctoral fellowship and prepare a specific research project or statement of interest under the umbrella of the lab research lines. We will be glad to work with you to support your applications.
  • While we appreciate ERASMUS or DAAD mobility programs, due to corona restrictions, lab space, and current lab composition, we have momentarily no openings at the technician, bachelor, or more senior postdoctoral level. We will advertise here and in all other channels when this changes. For general inquiries, please contact our secretary, who is generally well informed on developments in the lab.
  • For lung cancer-specific projects at the master and graduate student level, please also consider directly applying to Michela Serresi.

 

Due to the high volume of requests, despite our efforts to address each application, it is possible that our response may be delayed or may not occur. If you feel motivated to have a response and are well prepared on the lab scientific background and circumstances (see above), the most sensible approach is to alert our secretary on the matter.

Dr. Gaetano Gargiulo
Dr. Gaetano Gargiulo
Contact
Phone: +49 30 9406-3861
Max-Delbrück-Centrum für Molekulare Medizin (MDC)
Robert-Rössle-Straße 10
13125 Berlin, Deutschland
Building 31.1, Room 2027