TY - JOUR T1 - iPSC-derived Cancer Organoids Recapitulate Genomic and Phenotypic Alterations of c-<em>met</em>-mutated Hereditary Kidney Cancer JF - bioRxiv DO - 10.1101/518456 SP - 518456 AU - Jin Wook Hwang AU - Christophe Desterke AU - Olivier Féraud AU - Stephane Richard AU - Sophie Ferlicot AU - Virginie Verkarre AU - Jean Jacques Patard AU - Julien Loisel-Duwattez AU - Adlen Foudi AU - Frank Griscelli AU - Annelise Bennaceur-Griscelli AU - Ali G Turhan Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/01/11/518456.abstract N2 - Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis as a driving oncogenic event is present in germline, exposing the healthy member of a family to the occurrence of cancer. The study of the secondary events in a tissue-specific manner is now possible by the induced pluripotent stem cell (iPSC) technology offering the possibility to generate an unlimited source of cells that can be induced to differentiate towards a tissue at risk of malignant transformation. We report here for the first time, the generation of a c-met-mutated iPSC lines from the somatic cells of a patient with type 1 papillary renal cell carcinoma (PRCC). We demonstrate the feasibility of kidney differentiation with iPSC-derived organoids expressing markers of kidney progenitors with presence of tight junctions and brush borders in tubular structures at transmission electron microscopy. Importantly, c-met-mutated kidney organoids expressed PRCC markers both in vitro and in vivo in NSG mice. Gene expression profiling of c-met-mutated iPSC-derived organoid structures showed striking molecular similarities with signatures found in a large cohort of PRCC patient samples and identified 11 common genes. Among these, BHLHE40 and KDM4C, well-known factors involved in PRCC pathogenesis, were expressed in c-met-mutated kidney organoids. This analysis applied to primary cancers with and without c-met mutation showed overexpression of the BHLHE40 and KDM4C only in the c-met-mutated PRCC tumors, as predicted by c-met-mutated organoid transcriptome. These data represent therefore the first proof of concept of the generation of “renal carcinoma in a dish” model using c-met-mutated iPSC-derived organoids, opening new perspectives for discovery of novel potentially predictive disease markers and novel drugs for future precision medicine strategies. ER -