Spatial niche formation but not malignant progression is a driving force for intratumoural heterogeneity

Rouven Hoefflin, Bernd Lahrmann, Gregor Warsow, Daniel Hübschmann, Cathleen Spath, Britta Walter, Xin Chen, Luisa Hofer, Stephan Macher-Goeppinger, Yanis Tolstov, Nina Korzeniewski, Anette Duensing, Carsten Grüllich, Dirk Jäger, Sven Perner, Gita Schönberg, Joanne Nyarangi-Dix, Sanjay Isaac, Gencay Hatiboglu, Dogu Teber, Boris Hadaschik, Sascha Pahernik, Wilfried Roth, Roland Eils, Matthias Schlesner, Holger Sültmann, Markus Hohenfellner, Niels Grabe and Stefan Duensing ()
Additional contact information
Rouven Hoefflin: Section of Molecular Urooncology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg
Bernd Lahrmann: Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg
Gregor Warsow: German Cancer Research Center (DKFZ)
Daniel Hübschmann: German Cancer Research Center (DKFZ)
Cathleen Spath: National Center for Tumor Diseases
Britta Walter: University of Heidelberg School of Medicine
Xin Chen: Section of Molecular Urooncology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg
Luisa Hofer: University of Heidelberg School of Medicine
Stephan Macher-Goeppinger: University of Heidelberg School of Medicine
Yanis Tolstov: Section of Molecular Urooncology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg
Nina Korzeniewski: Section of Molecular Urooncology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg
Anette Duensing: University of Pittsburgh Cancer Institute, Cancer Therapeutics Program
Carsten Grüllich: National Center for Tumor Diseases
Dirk Jäger: National Center for Tumor Diseases
Sven Perner: Institute of Pathology, University Hospital Lübeck and Leibniz Research Center Borstel
Gita Schönberg: University of Heidelberg School of Medicine
Joanne Nyarangi-Dix: University of Heidelberg School of Medicine
Sanjay Isaac: National Center for Tumor Diseases
Gencay Hatiboglu: University of Heidelberg School of Medicine
Dogu Teber: University of Heidelberg School of Medicine
Boris Hadaschik: University of Heidelberg School of Medicine
Sascha Pahernik: University of Heidelberg School of Medicine
Wilfried Roth: University of Heidelberg School of Medicine
Roland Eils: German Cancer Research Center (DKFZ)
Matthias Schlesner: German Cancer Research Center (DKFZ)
Holger Sültmann: National Center for Tumor Diseases, German Cancer Research Center, German Cancer Consortium (DKTK)
Markus Hohenfellner: University of Heidelberg School of Medicine
Niels Grabe: Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg
Stefan Duensing: Section of Molecular Urooncology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Intratumoural heterogeneity (ITH) is a major cause of cancer-associated lethality. Extensive genomic ITH has previously been reported in clear cell renal cell carcinoma (ccRCC). Here we address the question whether ITH increases with malignant progression and can hence be exploited as a prognostic marker. Unexpectedly, precision quantitative image analysis reveals that the degree of functional ITH is virtually identical between primary ccRCCs of the lowest stage and advanced, metastatic tumours. Functional ITH was found to show a stage-independent topological pattern with peak proliferative and signalling activities almost exclusively in the tumour periphery. Exome sequencing of matching peripheral and central primary tumour specimens reveals various region-specific mutations. However, these mutations cannot directly explain the zonal pattern suggesting a role of microenvironmental factors in shaping functional ITH. In conclusion, our results indicate that ITH is an early and general characteristic of malignant growth rather than a consequence of malignant progression.

Date: 2016
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DOI: 10.1038/ncomms11845

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