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Drost group

The Drost group studies the molecular mechanisms underlying the development of childhood kidney and rhabdoid tumors and aims to identify novel therapies. We develop and utilize state-of-the-art pre-clinical cancer models, including 3D organoids, to study fundamental processes driving tumor growth, such as intratumor heterogeneity and therapy resistance.

PI: Dr. Jarno Drost
Phone +31 (0)88 9725503

Patient-derived organoids as models for pediatric renal and rhabdoid tumors

Kidney cancers represent approximately 6% of childhood cancers. The majority are Wilms tumors, representing about 90% of cases. Treatment of localized, non-anaplastic Wilms tumor is very successful. However, survival rates of certain Wilms tumor patient subgroups remain low and the harsh treatments result in severe side effects in survivors. The other pediatric kidney cancer subtypes (such as renal cell carcinoma and malignant rhabdoid tumors of the kidney) carry a dismal outcome profile as well. In addition to the kidney (MRTK), rhabdoid tumors can also appear in the brain (ATRT) and soft tissues (MRT). Rhabdoid tumors are rare, but very aggressive pediatric tumors and prognosis remains very poor. All this creates an urgent need for the development of new (and less toxic) therapies.

"Better models, increased knowledge: more cure!" Dr. Jarno Drost - PI

The organoid technology allows the unlimited in vitro expansion of healthy and diseased tissue from individual patients, while retaining key features of native tissue. The Drost group succeeded in growing organoids from a spectrum of pediatric tumors, including Wilms tumors, renal cell carcinomas, and rhabdoid tumors. Our renal and rhabdoid tumor organoids closely recapitulate the patient’s tumor and serve as unique models for cancer research and therapy development. We exploit these tumor organoid models to study fundamental processes underlying pediatric tumorigenesis (such as intratumor heterogeneity, metastasis and therapy resistance). Moreover, we use fetal kidney organoids combined with genome editing technologies (such as CRISPR/Cas9) to generate renal tumor progression models. Lastly, patient-derived organoids hold great promise for personalized medicine, drug discovery and the development of assays predicting treatment outcome. Currently, we are using our pediatric tumor organoids as a drug screening platform to identify novel (less toxic) therapies to treat children with cancer.

groep drost

H&E stainings on clear cell renal cell carcinoma tissue (left) and organoids derived thereof (right).


Dissecting the development of Wilms tumor heterogeneity

Wilms tumor is a typical example of a tumor that is the direct consequence of disturbance of normal development. They are characterized by a tri-phasic histology, comprising stromal, blastemal (progenitor) and epithelial components thought to result from incomplete differentiation during nephrogenesis. Using transgenic mouse models combined with imaging and single cell genomics & transcriptomics (in collaboration with the Holstege group), we aim to study tumor cell dynamics and to elucidate the signaling pathways deregulated in tumorigenesis.

Light microscope image of healthy human colon organoids (left). Color-coded confocal image of an H2B-mNeon-expressing cancer organoid to visualize chromosome segregations (right; Drost et al., Nature 2015).


Defining mutational signatures using genetically modified organoid cultures

Mutational processes contribute to cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We recently developed a strategy that can be used to explore the origin of cancer-associated mutational signatures by genetic modification of human organoid cultures using CRISPR/Cas9 and subsequent whole genome sequencing (Drost & van Boxtel et al., Science 2017). In collaboration with the van Boxtel and Kuiper groups, we are further applying this technology to determine mutational signatures in a wide range of childhood cancers. Moreover, we combine our strategy with drug screens to identify mutational signatures that predict resistance or hypersensitivity to genotoxic drugs.

The organoid technology provides an excellent pre-clinical model system for cancer research (Drost & Clevers, Nat. Rev. Cancer 2018). The Organoid Facility is embedded in the Drost group and supports organoid-based projects by offering quality tested conditioned media, growth factors and know-how. 

 

Members of the Drost group