University of Oulu

Xu, Q., Junttila, S., Scherer, A., Giri, K. R., Kivela, O., Skovorodkin, I., & Vainio, S. J. (2017). Renal carcinoma/kidney progenitor cell chimera organoid as a novel tumorigenesis gene discovery model. Disease Models & Mechanisms, 10 (12), 1503–1515. https://doi.org/10.1242/dmm.028332

Renal carcinoma/kidney progenitor cell chimera organoid as a novel tumorigenesis gene discovery model

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Author: Xu, Qi1; Junttila, Sanna1; Scherer, Andreas2;
Organizations: 1Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for Cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, Oulu University, FI-90014 Oulu, Finland
2Spheromics, FI-81100 Kontiolahti, Finland
3ValiFinn, FI-90220 Oulu, Finland
4Department of Computer Science and Engineering, University of Oulu, FI-90014 Oulu, Finland
5Feinberg Cardiovascular Research Institute, Division of Medicine-Nephrology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
6Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 12.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019041212052
Language: English
Published: Company of Biologists, 2017
Publish Date: 2019-04-12
Description:

Abstract

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.

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Series: Disease models & mechanisms
ISSN: 1754-8403
ISSN-E: 1754-8411
ISSN-L: 1754-8403
Volume: 10
Issue: 12
Pages: 1754 - 8403
DOI: 10.1242/dmm.028332
OADOI: https://oadoi.org/10.1242/dmm.028332
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
RCC
Funding: This project was supported by grants from the Academy of Finland (Suomen Akatemia; 206038, 121647), the Centre of Excellence Grant 251314 from the Academy of Finland for 2012–2017, FiDiPro (S.Q. 263246), the Sigrid Jusélius Foundation (Sigrid Juséliuksen Säätiö), the European Community's Seventh Framework Programme Health (FP7/2007-2013) under grant agreement FP7-HEALTH-F5-2012-INNOVATION-1 EURenOmics 305608, and the Cancer Society of Finland (Syöpäjärjestöt).
EU Grant Number: (305608) EURENOMICS - European Consortium for High-Throughput Research in Rare Kidney Diseases
Academy of Finland Grant Number: 206038
121647
251314
Detailed Information: 206038 (Academy of Finland Funding decision)
121647 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Copyright information: © 2017. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
  https://creativecommons.org/licenses/by/3.0/