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A Multi-Layered Systems Approach for Renal Cell Carcinoma

77 Pages Posted: 29 Apr 2020 Sneak Peek Status: Review Complete

See all articles by Lindsay S. Cooley

Lindsay S. Cooley

University of Bordeaux - LAMC

Justine Rudewicz

University of Bordeaux - LAMC

Wilfried Souleyreau

University of Bordeaux - LAMC

Kim Clarke

University of Liverpool - Institute of Integrative Biology

Francesco Falciani

University of Liverpool - Institute of Integrative Biology

Maeva Dufies

Centre Scientifique de Monaco

Stephanie Verbeke

University of Bordeaux - LAMC

Andrea Emanuelli

University of Bordeaux - LAMC

Sebastien Benzekry

Centre de Recherche Inria Bordeaux

Cecile Taing

Centre de Recherche Inria Bordeaux

Emeline-Julie Ribot

Center for Natural Resource Studies (CNRS) - Centre de Résonance Magnétique des Systèmes Biologiques (RMSB)

Sylvain Miraux

Center for Natural Resource Studies (CNRS) - Centre de Résonance Magnétique des Systèmes Biologiques (RMSB)

Diether Lambrechts

KU Leuven - VIB Center for Cancer Biology

Elodie Modave

KU Leuven - VIB Center for Cancer Biology

Raphael Pineau

University of Bordeaux

Marie-Alix Derieppe

University of Bordeaux

Damien Ambrosetti

Centre Hospitalier Universitaire (CHU) de Nice

Jean-Christophe Bernhard

Centre Hospitalier Universitaire (CHU) de Bordeaux

Alain Ravaud

Centre Hospitalier Universitaire (CHU) de Bordeaux

Sylvie Négrier

University of Claude Bernard Lyon 1 - Centre Léon Bérard

Jean-Marc Ferrero

Centre Antoine Lacassagne

Gilles Pagès

Centre Scientifique de Monaco

Macha Nikolski

University of Bordeaux - Bordeaux Bioinformatics Center; University of Bordeaux - CNRS, LaBRI

Andreas Bikfalvi

University of Bordeaux - LAMC

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Abstract

Renal cell carcinoma (RCC) still lacks prognostic and predictive biomarkers to monitor the disease and the response to therapy. The usual strategy in translational research is to start from human samples, to identify molecular markers and gene networks and then to functionally validate them in vitro and in animal models. We devised herein a completely opposite strategy from “mouse to man” by performing an aggressiveness screen and used functional genomics, imaging, clinical data and computational approaches in order to discover molecular pathways and players in renal cancer development and metastasis. Multiple cell lines for primary tumor growth, survival in the blood circulation and lung metastasis or metastatic spread from the primary tumor were generated and analyzed using a multi-layered approach which includes large-scale transcriptome, genome and methylome analyses. Transcriptome and methylome analyses demonstrated distinct clustering in three different groups. Remarkably, DNA sequencing did not show significant genomic variations in the different groups which indicates absence of clonal selection during the in vivo amplification process. Transcriptome analysis revealed distinct signatures of tumor aggressiveness which were validated in patient cohorts. Methylome analysis of full-length DNA allowed clustering of the same groups and revealed clinically relevant signatures. Furthermore, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. We also uncovered IL34 as another soluble prognostic biomarker and key regulator of renal cell carcinoma (RCC) progression. This was also functionally validated in vivo, and a mathematical model of IL34-dependent primary tumor growth and metastasis development was provided. These results indicate that such multilayered analysis in a RCC animal model leads to meaningful results that are of translational significance.

Keywords: Renal cell carcinoma, agressivness screen, metastasis, tumor model, multi-layer approach

Suggested Citation

Cooley, Lindsay S. and Rudewicz, Justine and Souleyreau, Wilfried and Clarke, Kim and Falciani, Francesco and Dufies, Maeva and Verbeke, Stephanie and Emanuelli, Andrea and Benzekry, Sebastien and Taing, Cecile and Ribot, Emeline-Julie and Miraux, Sylvain and Lambrechts, Diether and Modave, Elodie and Pineau, Raphael and Derieppe, Marie-Alix and Ambrosetti, Damien and Bernhard, Jean-Christophe and Ravaud, Alain and Négrier, Sylvie and Ferrero, Jean-Marc and Pagès, Gilles and Nikolski, Macha and Bikfalvi, Andreas, A Multi-Layered Systems Approach for Renal Cell Carcinoma. Available at SSRN: https://ssrn.com/abstract=3577243 or http://dx.doi.org/10.2139/ssrn.3577243
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Lindsay S. Cooley

University of Bordeaux - LAMC

France

Justine Rudewicz

University of Bordeaux - LAMC

France

Wilfried Souleyreau

University of Bordeaux - LAMC

France

Kim Clarke

University of Liverpool - Institute of Integrative Biology

Liverpool, L69 7ZB
United Kingdom

Francesco Falciani

University of Liverpool - Institute of Integrative Biology ( email )

Liverpool, L69 7ZB
United Kingdom

Maeva Dufies

Centre Scientifique de Monaco ( email )

Monaco

Stephanie Verbeke

University of Bordeaux - LAMC ( email )

France

Andrea Emanuelli

University of Bordeaux - LAMC ( email )

France

Sebastien Benzekry

Centre de Recherche Inria Bordeaux

200 Avenue de la Vieille Tour
Talence, 33405
France

Cecile Taing

Centre de Recherche Inria Bordeaux

200 Avenue de la Vieille Tour
Talence, 33405
France

Emeline-Julie Ribot

Center for Natural Resource Studies (CNRS) - Centre de Résonance Magnétique des Systèmes Biologiques (RMSB)

France

Sylvain Miraux

Center for Natural Resource Studies (CNRS) - Centre de Résonance Magnétique des Systèmes Biologiques (RMSB)

France

Diether Lambrechts

KU Leuven - VIB Center for Cancer Biology

Leuven
Belgium

Elodie Modave

KU Leuven - VIB Center for Cancer Biology

Leuven
Belgium

Raphael Pineau

University of Bordeaux

Avenue Léon Duguit
Bordeaux, 33000
France

Marie-Alix Derieppe

University of Bordeaux

Avenue Léon Duguit
Bordeaux, 33000
France

Damien Ambrosetti

Centre Hospitalier Universitaire (CHU) de Nice

Nice
France

Jean-Christophe Bernhard

Centre Hospitalier Universitaire (CHU) de Bordeaux

Place Amélie Raba Léon
Bordeaux
France

Alain Ravaud

Centre Hospitalier Universitaire (CHU) de Bordeaux

Place Amélie Raba Léon
Bordeaux
France

Sylvie Négrier

University of Claude Bernard Lyon 1 - Centre Léon Bérard

28 Rue Laennec
Lyon, 69008
France

Jean-Marc Ferrero

Centre Antoine Lacassagne

Nice
France

Gilles Pagès

Centre Scientifique de Monaco

Monaco

Macha Nikolski

University of Bordeaux - Bordeaux Bioinformatics Center

Bordeaux
France

University of Bordeaux - CNRS, LaBRI

Talence
France

Andreas Bikfalvi (Contact Author)

University of Bordeaux - LAMC ( email )

France

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