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 TeberBoris Hadaschik, Sascha Pahernik, Wilfried Roth, Roland Eils, Matthias Schlesner, Holger Sültmann, Markus Hohenfellner, Niels Grabe, Stefan Duensing*

*Corresponding author for this work
21 Citations (Scopus)


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.

Original languageEnglish
Article numberncomms11845
JournalNature Communications
Publication statusPublished - 13.06.2016


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