Gargiulo Lab

In other words, we want to understand how tumor tissues balance self-growth with interactions with the host. These processes sustain cancer survival and govern critical cell decisions, including whether cancer cells self-renew, differentiate, adapt, or die. In this sense, tumor homeostasis can be viewed as the dark side of normal tissue self-regulation.

We also investigate how cancer cells cope with therapy-induced stress.

Understanding these mechanisms will help us identify cancer-specific vulnerabilities and may pave the way toward more effective treatments.

Background

Cancer arises from genetic and epigenetic alterations, and evolves through dynamic cell-state plasticity. Our research focuses on the molecular mechanisms that regulate tumor homeostasis, microenvironmental crosstalk, and response to anti-cancer therapy.

In other words, we seek to understand how tumor tissues balance self-growth with interactions with the host. These processes sustain cancer survival and govern critical cell decisions, including whether cancer cells self-renew, differentiate, adapt, or die. In this sense, tumor homeostasis can be viewed as the dark side of normal tissue self-regulation.

We also investigate how cancer cells cope with therapy-induced stress and how these adaptive responses contribute to disease progression and treatment resistance.

Understanding these mechanisms will help identify cancer-specific vulnerabilities and may pave the way toward more effective therapies.

Approach

Our research combines oncology and technology development to understand how cancer cell identities emerge, change, and interact with the tumor microenvironment.

We study solid tumors, with a particular focus on glioblastoma and KRAS-driven lung cancer, while developing experimental and computational technologies that enable functional interrogation of cancer cell states. These include synthetic genetic tracing systems, genetic screens in vitro and in vivo, and phenotypic drug discovery platforms (Figure).

Together, these approaches allow us to investigate:

• Genotype-to-molecular phenotype connections

• Molecular and cellular heterogeneity

• Mechanisms of tumor homeostasis and plasticity

• Signaling-to-chromatin regulatory circuits

• Target discovery and validation

Our long-term goal is to identify actionable vulnerabilities that emerge from cancer cell-state dynamics and tumor – microenvironment interactions.

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 glioblastoma (GBM). 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 studying cell states and microenvironmental interactions, 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 emerging after 40 years, but still largely benefit selected patients.

What we discovered

Over the past years, our work has contributed to several conceptual advances in cancer biology:

• Brain tumors such as GBM are shaped by the interaction between genetic alterations and dynamic and reversible cancer cell states (Schmitt M., Company C., Dramaretska Y., et al., Cancer Discovery 2021).

• Chromatin regulators act as critical gatekeepers of cancer cell-state plasticity and epithelial – mesenchymal transitions (Serresi et al., Science Advances 2021).

• Synthetic genetic tracing enables functional mapping of cell identities and state transitions in living systems (Glioblastoma : Schmitt M., et al., Cancer Discovery 2021; Lung cancer: Serresi et al., Science Adv. 2021; COVID-19: Jiang B., Schmitt M., et al., Science Adv. 2023; Colon cancer: Mzoughi et al., Nature Genetics 2025 (w/​Guccione lab); Technology development: Company C., Schmitt M., Dramaretska Y., Serresi et al., et al., Nature Comm., 2024; PCT/EP2019/073711.

• Crosstalk between cancer cells and the tumor microenvironment can drive adaptive state transitions associated with therapeutic resistance (Schmitt M., Company C., Dramaretska Y., et al., Cancer Discovery 2021).

• Quantitative changes in oncogenic signaling can control tumor evolution by directing distinct cellular states (Serresi et al., biorXiv. 2024 — preprint).

These findings support a view of cancer as a dynamic ecosystem in which cell identity, plasticity, and microenvironmental interactions play central roles in disease progression and treatment response.

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 54^th 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.