PMID- 29084770 OWN - NLM STAT- MEDLINE DCOM- 20180727 LR - 20181113 IS - 1754-8411 (Electronic) IS - 1754-8403 (Print) IS - 1754-8403 (Linking) VI - 10 IP - 12 DP - 2017 Dec 19 TI - Renal carcinoma/kidney progenitor cell chimera organoid as a novel tumorigenesis gene discovery model. PG - 1503-1515 LID - 10.1242/dmm.028332 [doi] AB - Three-dimensional (3D) organoids provide a new way to model various diseases, including cancer. We made use of recently developed kidney-organ-primordia tissue-engineering technologies to create novel renal organoids for cancer gene discovery. We then tested whether our novel assays can be used to examine kidney cancer development. First, we identified the transcriptomic profiles of quiescent embryonic mouse metanephric mesenchyme (MM) and of MM in which the nephrogenesis program had been induced ex vivo The transcriptome profiles were then compared to the profiles of tumor biopsies from renal cell carcinoma (RCC) patients, and control samples from the same kidneys. Certain signature genes were identified that correlated in the developmentally induced MM and RCC, including components of the caveolar-mediated endocytosis signaling pathway. An efficient siRNA-mediated knockdown (KD) of Bnip3, Gsn, Lgals3, Pax8, Cav1, Egfr or Itgb2 gene expression was achieved in mouse RCC (Renca) cells. The live-cell imaging analysis revealed inhibition of cell migration and cell viability in the gene-KD Renca cells in comparison to Renca controls. Upon siRNA treatment, the transwell invasion capacity of Renca cells was also inhibited. Finally, we mixed E11.5 MM with yellow fluorescent protein (YFP)-expressing Renca cells to establish chimera organoids. Strikingly, we found that the Bnip3-, Cav1- and Gsn-KD Renca-YFP+ cells as a chimera with the MM in 3D organoid rescued, in part, the RCC-mediated inhibition of the nephrogenesis program during epithelial tubules formation. Altogether, our research indicates that comparing renal ontogenesis control genes to the genes involved in kidney cancer may provide new growth-associated gene screens and that 3D RCC-MM chimera organoids can serve as a novel model with which to investigate the behavioral roles of cancer cells within the context of emergent complex tissue structures. CI - (c) 2017. Published by The Company of Biologists Ltd. FAU - Xu, Qi AU - Xu Q AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland. FAU - Junttila, Sanna AU - Junttila S AUID- ORCID: 0000-0002-2642-3760 AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland. FAU - Scherer, Andreas AU - Scherer A AD - Spheromics, FI-81100 Kontiolahti, Finland. FAU - Giri, Khem Raj AU - Giri KR AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland. FAU - Kivela, Oona AU - Kivela O AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland. AD - ValiFinn, FI-90220 Oulu, Finland. FAU - Skovorodkin, Ilya AU - Skovorodkin I AUID- ORCID: 0000-0003-1182-1130 AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland. FAU - Roning, Juha AU - Roning J AD - Department of Computer Science and Engineering, University of Oulu, FI-90014 Oulu, Finland. FAU - Quaggin, Susan E AU - Quaggin SE AUID- ORCID: 0000-0002-3706-5727 AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland. AD - Feinberg Cardiovascular Research Institute, Division of Medicine-Nephrology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. FAU - Marti, Hans-Peter AU - Marti HP AUID- ORCID: 0000-0002-6331-5902 AD - Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway. FAU - Shan, Jingdong AU - Shan J AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland. FAU - Samoylenko, Anatoly AU - Samoylenko A AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland anatoliy.samoylenko@oulu.fi seppo.vainio@oulu.fi. FAU - Vainio, Seppo J AU - Vainio SJ AUID- ORCID: 0000-0001-9319-3566 AD - Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland anatoliy.samoylenko@oulu.fi seppo.vainio@oulu.fi. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171219 PL - England TA - Dis Model Mech JT - Disease models & mechanisms JID - 101483332 RN - 0 (Biomarkers, Tumor) RN - 0 (RNA, Small Interfering) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Biomarkers, Tumor/metabolism MH - Carcinogenesis/*genetics/*pathology MH - Carcinoma, Renal Cell/genetics/*pathology MH - Cell Differentiation MH - Cell Line, Tumor MH - Cell Movement/genetics MH - Chimera/*metabolism MH - Coculture Techniques MH - Disease Models, Animal MH - Epithelial-Mesenchymal Transition/genetics MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic MH - Gene Silencing MH - *Genetic Association Studies MH - HEK293 Cells MH - Humans MH - Kidney/*pathology MH - Kidney Neoplasms/genetics/*pathology MH - Mice MH - Neoplasm Invasiveness MH - Nephrons/pathology MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/metabolism MH - RNA, Small Interfering/metabolism MH - Stem Cells/*pathology MH - Transfection MH - Tumor Stem Cell Assay PMC - PMC5769601 OTO - NOTNLM OT - Gene expression OT - Nephrogenesis OT - RCC OT - Renal cell carcinoma OT - siRNA COIS- Competing interestsThe authors declare no competing or financial interests. EDAT- 2017/11/01 06:00 MHDA- 2018/07/28 06:00 PMCR- 2017/12/01 CRDT- 2017/11/01 06:00 PHST- 2016/10/18 00:00 [received] PHST- 2017/10/16 00:00 [accepted] PHST- 2017/11/01 06:00 [pubmed] PHST- 2018/07/28 06:00 [medline] PHST- 2017/11/01 06:00 [entrez] PHST- 2017/12/01 00:00 [pmc-release] AID - dmm.028332 [pii] AID - DMM028332 [pii] AID - 10.1242/dmm.028332 [doi] PST - epublish SO - Dis Model Mech. 2017 Dec 19;10(12):1503-1515. doi: 10.1242/dmm.028332.