PI: Dr. Jarno Drost
more cure!" Dr. Jarno Drost - PI
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. However, therapeutic innovation is hampered by the lack of cell models representative of native tumor tissue.
Organoids as representative models for pediatric renal and rhabdoid tumors
The organoid technology has revolutionized cancer research, as it allows for the ‘unlimited’ in vitro expansion of healthy and diseased tissue from individual patients while retaining essential characteristics of native tissue. We were the first in the world to apply organoid technology to childhood cancers and succeeded in growing organoids from a spectrum of pediatric tumors including Wilms tumors, renal cell carcinomas, and different rhabdoid tumor subtypes. We establish organoid models from all prospectively collected kidney and rhabdoid tumor samples derived from patients treated in our center. We use these models to study the very fundamental processes underlying tumorigenesis, as well as for more translational research projects.
Besides tumor organoids, we also use healthy tissue-derived organoids for the generation of tumor models. We apply different genome editing technologies (such as CRISPR/Cas9 technology) to healthy organoids to generate kidney tumor progression models, as we have previously described for colorectal cancer (see video below). Such engineered tumor organoids provide genetically defined models that allow for studying the contribution of specific genetic alterations to tumorigenesis. We are also applying this technology to study mutational signatures in a wide range of childhood cancers and childhood cancer predisposition syndromes.
Developing new therapeutic strategies for renal and rhabdoid tumors using organoids
The efficient establishment of organoids from patient-derived tumor tissues allows for the development of personalized therapies. We perform high-throughput drug testing on patient-derived tumor organoids using an in-house robotics platform (HTS facility) to test multiple drugs at the same time without burdening the patient. Using this platform, we aim to identify novel, less toxic therapies to treat children with cancer. By performing drug screens on tumor-derived as well as healthy tissue-derived organoids, we select drugs that selectively target tumor cells while leaving healthy cells unharmed. In vivo (mouse models) and mechanistic studies are subsequently performed to validate our findings and to investigate the underlying mechanisms. We also exploit our organoid models for the development of antibody-based therapies and cell-based immunotherapies (collaboration with the Janda group) by generating co-cultures of tumor organoids and different types of immune cells (e.g. TILs and CAR-T cells).
Dissecting the cellular origin and molecular mechanisms underpinning tumor initiation and progression
Many childhood tumors are thought to arise during embryogenesis and to be underpinned by genetic alterations causing a block in differentiation and unrestricted proliferation. In many cases, however, the cellular identity as well as the responsible molecular signaling pathways remain unknown. We take a multidisciplinary approach and combine our unique preclinical models (i.e. organoids and mouse models) with (single-cell) (epi-) genomics & transcriptomics, genetic lineage tracing, CRISPR screens and 3D imaging to understand how these tumors develop during embryonic development and how they acquire metastatic capacity and therapy resistance.
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.
Young MD*,#, Mitchell TJ*, Custers L*, Khabirova E, Oliver TRW, Comitani F, Piapi A, Bugallo Blanco E, Thevanesan C, Roberts K, Braga FAV, Coorens THH, Del Valle I, WilbreyClark A, Mamanova L, Stewart GD, Gnagapragasam VJ, Rampling D, Sebire N, Coleman N, Hook L, Warren A, Haniffa M, Kool M, Pfister SM, Achermann JC, He X, Barker RA, Shlien A, Bayraktar OA, Teichmann S, Meyer KB, Drost J#, Straathof K#, Behjati S#. Cellular mRNA signals in human kidney tumors. (2020) BioRxiv doi.org/10.1101/2020.03.19.998815
Calandrini C*, Schutgens F*, Oka R, Margaritis T, Candelli T, Mathijsen L, Ammerlaan C, van Ineveld RL, Derakhshan S, de Haan S, Dolman E, Lijnzaad P, Custers L, Begthel H, Kerstens HHD, Rookmaker M, Verhaar M, Tytgat GAM, Kemmeren P, de Krijger RR, Al-Saadi R, Pritchard-Jones K, Kool M, Rios A, van den Heuvel-Eibrink MM, Molenaar J, van Boxtel R, Holstege FCP, Clevers H, Drost J#. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity. (2020) Nature Communications 11: 1310. doi: 10.1038/s41467-020-15155-6.
Drost J#, Clevers H. Organoids in cancer research. (2018) Nature Reviews Cancer 18: 407 – 418.
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.
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.
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.
* Equal contribution
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