iPSC-derived Cancer Organoids Recapitulate Genomic and Phenotypic Alterations of c-met-mutated Hereditary Kidney Cancer

Hwang, J. W.; Desterke, C.; Feraud, O.; Richard, S.; Ferlicot, S.; Verkarre, V.; Patard, J. J.; Loisel-Duwattez, J.; Foudi, A.; Griscelli, F.; Bennaceur Griscelli, A.; Turhan, A. G.

doi:10.1101/518456

bioRxiv · 10.1101/518456

iPSC-derived Cancer Organoids Recapitulate Genomic and Phenotypic Alterations of c-met-mutated Hereditary Kidney Cancer

Hwang, J. W.·Desterke, C.·Feraud, O.·Richard, S.·Ferlicot, S.·Verkarre, V.·Patard, J. J.·Loisel-Duwattez, J.·Foudi, A.·Griscelli, F.·Bennaceur Griscelli, A.·Turhan, A. G.

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Abstract

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.

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Hwang, J. W., Desterke, C., Feraud, O., Richard, S., Ferlicot, S., Verkarre, V., Patard, J. J., Loisel-Duwattez, J., Foudi, A., Griscelli, F., Bennaceur Griscelli, A., Turhan, A. G.. 2019-01-11. iPSC-derived Cancer Organoids Recapitulate Genomic and Phenotypic Alterations of c-met-mutated Hereditary Kidney Cancer. https://doi.org/10.1101/518456

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