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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)
Jan 2004 to Dec 2005: Postdoctoral fellow, Division of Experimental Oncology II, (Group: Prof. Pier Paolo Di Fiore), European Institute of Oncology, Milan, Italy
Sep 2001 to Dec 2003: Visiting Scientist at the European Institute of Oncology, Milan, Italy (Group: Prof. Pier Paolo Di Fiore)
Jan 2000 to Dec 2003: Pre-doctoral research position in the laboratory of Molecular biology (Group: Prof, Francesca Fazioli), Universita’ Politecnica delle Marche, Ancona, Italy.

Awards and Honours

  • 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

Jikke Wierikx
Student AVANS University of Applied Sciences, The Netherlands

Selected publications

Polycomb and lung cancer: when the dosage makes the (kind of) poison
Gargiulo G, Citterio E, Serresi M
Mol Cell Oncol 2016 Feb, 24  DOI:10.1080/23723556.2016.1152345

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 and van Lohuizen M
Cancer Cell 2016 Jan 11;29(1):17-31. doi: 10.1016/j.ccell.2015.12.006.

In vivo shRNA screens in solid tumors.
Gargiulo G, Serresi M, Cesaroni M, Hulsman D, van Lohuizen M
Nature Protocol 2014 Dec 9;(12): 2880-902

Tight regulation of the ubiquitin-mediated DNA damage response pathway by USP3 preserves the functional integrity of hematopoietic stem cell. Lancini C, van den Berk P, Vissers JH, Gargiulo G, Song JY, Hulsman D, Serresi M, Tanger E, Blom M, Vens C, van Lohuizen M, Jacobs H and Citterio E
Journal of Experimental Medicine 2014 Aug 25; 211(9):1759-77.

In vivo RNAi screen for BMI1 targets identifies TGF-B/BMP-ER stress pathway 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

Dr. Gaetano Gargiulo
Dr. Gaetano Gargiulo