PI: Dr. Jarno Drost
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.
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.
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.
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.
Drost J#, Clevers H. Organoids in cancer research. (2018) Nature Reviews Cancer Apr 24. Press here for the full text version of the article.
Fumagalli A, Suijkerbuijk SJE, Begthel H, Beerling E, Oost KC, Snippert HJ, van Rheenen J#, Drost J#. An orthotopic organoid transplantation approach in mice to visualize and study colorectal cancer progression. (2018) Nature Protocols 13: 235 – 247. Press here for the full text version of the article.
Drost J*, van Boxtel R*, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, de Ligt J, Behjati S, Grolleman JE, van Wezel T, Nik-Zainal S, Kuiper RP, Cuppen E, Clevers H. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. (2017) Science 358: 234 – 238. Press here for the full text version of the article.
Fumagalli A*, Drost J*, Suijkerbuijk SJE, van Boxtel R, de Ligt J, Offerhaus GJ, Begthel H, Tan EH, Sansom OJ, Cuppen E, Clevers H, van Rheenen J. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. (2017) Proceedings of the National Academy of Sciences of the United States of America Mar 7. pii: 201701219. Press here for the full text version of the article.
Drost J, van Jaarsveld RH, Ponsioen B, Zimberlin C, van Boxtel R, Buijs A, Sachs N, Overmeer RM, Offerhaus GJ, Begthel H, Korving J, van de Wetering M, Schwank G, Logtenberg M, Cuppen E, Snippert HJ, Medema JP, Kops GJPL, Clevers H. Sequential cancer mutations in cultured human intestinal stem cells. (2015) Nature 521:43 – 47. Press here for the full text version of the article.
* Equal contribution
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