Exosomes Research Group (ERG)

The Exosomes Research group (ERG) headed by Michiel Pegtel is a multi-disciplinary laboratory focusing on cancer biology, cancer immunology and autoimmunity. The research lines are connected by the recent realization that most cells secrete small vesicles called 'exosomes' that have a key role in many biological processes and can be exploited useful for clinical purposes. Michiel Pegtel is also the director of the Amsterdam UMC Liquid biopsy center (LBC) which collects stores biofluids from patients with cancer for research and development of minimally-invasive diagnostic methods.
For more information visit www.exosomes.nl and www.liquidbiopsycenter.nl
For internships please contact Michiel Pegtel d.pegtel@vumc.nl (master students) or
Monique van Eijndhoven m.vaneijndhoven@vumc.nl (HLO students)

1. Tumor exosomes Biology and the microenvironment.

Staff/lead investigators; Michiel Pegtel, Rubina Baglio

The tumor microenvironment takes part in virtually every aspect of cancer development and progression, including metastasis formation and resistance to therapeutics including checkpoint inhibitors. Mesenchymal stem cells (MSCs) are established contributors to malignant dissemination in breast cancer, brain tumors, colon cancer, multiple myeloma and osteosarcoma a devastating tumor of bone tissue that affects children. MSCs are adult stem cells that can home to sites of inflammation, where in response to environmental cues they can differentiate into cancer-supporting cells. We are trying to understand this process using pre-clinical mouse models developing multiple strategies to target the tumor-stoma to stop metastasis. To discover how tumor cells secrete exosomes we developed a unique live-imaging approach that can study tumor cell behavior at the single cells level which is suitable for Crispr/Cas screening. Super-resolution and electron microscopy is used to characterize tumor exosomes heterogeneity at the single particle level.

2. Exosomes and small non-coding RNAs.

Staff; Michiel Pegtel

The development of human cancers relies in part on the ability to survive in an inhospitable microenvironment. Intercommunication between the tumor cells and their surrounding microenvironment is essential to overcoming this obstacle and for the tumor to progress, metastasize and establish itself at distant sites. Exosomes carry lipids, proteins, mRNAs and microRNAs (miRNA) that can be transferred to a recipient cell via fusion of the exosome with target cells. This process entails transfer of cancer-supporting cellular content from tumor cancer cells to neighboring stroma cells within the tumor microenvironment or into the circulation to act at distant sites for example by education of the bone-marrow cells. The transfer of exosomal miRNAs to a recipient cell where they can control gene expression is of high interest, both in understanding the biology of cancer progression and for the development of therapeutic approaches. We use advanced sequencing methods to characterize the small RNA content of exosomes. We aim to unravel how small RNA sorting and transmission via exosomes in the tumor microenvironment and autoimmune disease drives chronic inflammation and therapy resistance. We exploit this knowledge to investigate molecular mechanisms of exosomes and small RNA content in cancer (mouse) models and validate these findings in clinical specimens such as tissue sections and biofluids.

3. Liquid Biopsy.

Staff; Michiel Pegtel, Florent Mouliere

Nowadays, cancer is still diagnosed through painful and invasive tissue biopsies of a suspected mass. Additional (repeat) tissue biopsies are sometimes necessary in the follow up, increasing the chance of complications.

By making use of the Liquid Biopsy Center initiative, we aim to develop and test novel non-invasive methods for detecting cancer in biofluids. Dr Pegtel focuses how exosomal small RNAs in cancer patient biofluids can be exploited used for diagnosis, assessment of prognosis, early detection of disease recurrence. To achieve this we study how miRNAs and other ncRNA species are stabilized and secreted into human biofluids (blood, urine and CSF) and make predictions on their origin. Dr Mouliere focuses his research on cell-free DNA. Circulating tumor DNA (ctDNA) make up a small fraction of cfDNA and is now being extensively studied as a noninvasive "real-time" biomarker that can provide diagnostic and prognostic information before, during treatment and at progression. These include cancer-specific DNA mutations, epigenetic alterations and other forms of tumor-specific abnormalities such as microsatellite instability (MSI) and loss of heterozygosity (LOH). ctDNA is of great value in the process of cancer treatment and supported by the CCA-LBC, Dr Florent's major aim is to develop low-cost, easily applicable solutions for non-invasive cancer diagnostics. To this end new cfDNA and ctDNA enrichment strategies are developed including smart design of new detection techniques, improving current sequencing approaches and use artificial intelligence to mine sequencing data from the plasma of patients with cancer. Ultimately these tests can be utilized for earlier cancer diagnosis, more accurate cancer prognosis and better treatment selection.

Exosomes Research Group (ERG)