Abstract 3688: iPSC-derived cancer organoids recapitulate genomic and phenotypic alterations of c-Met-mutated hereditary kidney cancer
Authors: Hwang Jin Wook , Desterke Christophe , Feraud Olivier , Richard Stephane , Ferlicot Sophie , Verkarre Virginie , Patard Jean Jacques , Loisel-Duwattez Julien , Foudi Adlen , Griscelli Frank , Griscelli Annelise Bennaceur , Turhan Ali G. 
Published: August 2019

Patient-specific, tumor-derived organoids represent a powerful novel technology to model cancer, but the requirement of collection of fresh tumor cells and low efficiency of organoid generation represents significant bottlenecks. The induced pluripotent stem cell (iPSC) technology offers the possibility to generate an unlimited and reproducible source of cancer organoids from patient-derived iPSC bearing an oncogenic mutation. We report here for the first time, the generation of patient-specific iPSC-derived kidney organoids in type 1 papillary renal cell carcinoma (PRCC) with hereditary c-met-mutation. To this end we first reprogrammed hematopoietic cells of a patient with type 1 PRCC using Oct4, Sox2, Klf4 and c-Myc. The iPSC cell line generated teratoma in NSG mice and expressed pluripotency markers Tra-1-60 and SSEA-4. As compared control iPSC lines, the c-Met mutated iPSC expressed high levels of phosphorylated c-Met protein. To determine the feasibility of generation of kidney organoids from the iPS cells we have used 3D culture in low attachment cultures giving rise to organoids expressing markers of kidney progenitors (PODXL, LTL) with presence of tight junctions and brush borders in tubular structures at transmission electron microscopy. Importantly, the c-met-mutated kidney organoids expressed PRCC markers in vitro with presence of cells expressing cytokeratin 7 and TFE3. When injected under the kidney capsule of NSG mice, c-met-mutated kidney organoids generated teratomas in which we have found structures with glomerular or tubular origin of such structures with the expression of Nephrin and Cytokeratin 7. 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 the expression of 11 common genes shared with c-Met-mutated iPSC-derive organoids and primary cancers. Among these, BHLHE40 and KDM4C, well-known factors involved in PRCC pathogenesis, were also expressed in tumors obtained in vivo after transplantation of c-met-mutated kidney organoids in immunodeficient mice. To determine the expression of these two markers discovered by the iPSC-derived organoid technology, we have analyzed tumor biopsies from 5 primary PRCC wit and without c-MET mutation. This analysis 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 disease markers and novel drugs for future precision medicine strategies.

Note: This abstract was not presented at the meeting.

Citation Format: Jin Wook Hwang, Christophe Desterke, Olivier Feraud, Stephane Richard, Sophie Ferlicot, Virginie Verkarre, Jean Jacques Patard, Julien Loisel-Duwattez, Adlen Foudi, Frank Griscelli, Annelise Bennaceur Griscelli, Ali G. Turhan. iPSC-derived cancer organoids recapitulate genomic and phenotypic alterations of c-Met-mutated hereditary kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3688.