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Spatial heterogeneity and therapy resistance in lung cancer


For many years, we have been cooperating with partners at the Thoraxklinik Heidelberg, working on different molecular alterations and clinical translation in lung cancer (NSCLC). This has enabled us to obtain sustainable funding in the German Center for Lung Diseases (DZL), which provides a secure basis for our future translational lung cancer research. In cooperation with the Thoraxklinik, the Pathology Department Heidelberg and the Weizmann Institute of Science (Israel), we investigated the mutational and epigenomic heterogeneity of NSCLC (Dietz et al., Int J Cancer 141(9):1841-1848, 2017; Dietz et al, Int J Cancer, 2019): Using a meta-analysis with TCGA data, we found that the entire range of epigenomic heterogeneity was represented in our small sample set of 40 tissue regions from only seven patients.


Selected Publications:

  • Dietz S, Lifshitz A, Kazdal D, Harms A, Endris V, Winter H, Stenzinger A, Warth A, Sill M, Tanay A, Sültmann H. Global DNA methylation reflects spatial heterogeneity and molecular evolution of lung adenocarcinomas. Int J Cancer 144(5):1061-1072, 2019
  • Dietz S, Harms A, Endris V, Eichhorn F, Kriegsmann M, Longuespée R, Stenzinger A, Sültmann H, Warth A, Kazdal D. Spatial distribution of EGFR and KRAS mutation frequencies correlates with histological growth patterns of lung adenocarcinomas. Int J Cancer 141(9):1841-1848, 2017


Our recent efforts investigating tumor heterogeneity and its influence on resistance to tyrosine kinase inhibitors (TKI) focussed on the establishment and application of 3D coculture models (spheroids of ALK-fusion-positive tumor cells with cancer associated fibroblasts (CAFs)). Using a combination of scRNA-seq, epigenomics, MS-based proteomics and metabolomics technologies, we identified several novel ligand-receptor interactions between CAFs and tumor cells (Ann-Kathrin Daum, PhD thesis, Heidelberg, 2021; paper in preparation).

Cooperations: Thoraxklinik Heidelberg; Dept. of Pathology at Heidelberg University Medical Center

Support: German Federal Ministry for Education and Research (BMBF) in the funding programs German Centers for Lung Research (DZL), Medical Systems Biology (PREDICT), and eBio (EPITREAT).



Liquid Biopsy for noninvasive tumor monitoring and detection of minimal residual disease


We have augmented and extended our liquid biopsy approaches towards the establishment and application of liquid biopsy technologies for tumor monitoring and detection of minimal residual disease (MRD). To this end, we used ca. 500 longitudinal plasma samples from ALK-fusion-positive lung cancer patients (cooperation with the Thoraxklinik Heidelberg) as a proof of principle study to:


• determine single nucleotide variants (SNVs) and copy number variants in plasma DNA (Dietz et al, EBioMedicine, 2020),
• correlate molecular data with clinical parameters like oligoprogression (Christopoulos et al, Transl Lung Cancer Res, 2021),
• show that the molecular lead time to progression under therapy is shorter compared to radiological lead time (Angeles et al, NPJ Precis Oncol, 2021),
• identify epigenomic variants to detection tumor progression and MRD (Janke et al, Clin Epigenet, 2022).


Selected publications:


  • Angeles AK, Janke F, Daum AK, Reck M, Schneider MA, Thomas M, Christopoulos P, Sültmann H. Integrated circulating tumour DNA and cytokine analysis for therapy monitoring of ALK-rearranged lung adenocarcinoma. Br J Cancer, doi:10.1038/s41416-023-02284-0, 2023
  • Janke F, Angeles AK, Riediger AL, Bauer S, Reck M, Schneider MA, Muley T, Thomas M, Christopoulos P, Sültmann H. Monitoring progression of ALK-rearranged lung adenocarcinoma using DNA methylation patterns in cell free DNA. Clinical Epigenetics, 14(1):163, 2022
  • Angeles AK*, Christopoulos P*, Yuan Z, Bauer S, Janke F, Ogrodnik SJ, Reck M, Schlesner M, Meister M, Schneider MA, Dietz S, Stenzinger A, Thomas M, Sültmann H. Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis.NPJ Precision Oncology, 5(1):100, 2021
  • Dietz S, Christopoulos P, Yuan Z, Gu L, Volckmar A-L, Ogrodnik SJ, Angeles AK, Dalle Fratte C, Zemojtel T, Schneider MA, Kazdal D, Endris V, Meister M, Muley T, Cecchin E, Reck M, Schlesner M, Thomas M, Stenzinger A, Sültmann H. Longitudinal therapy monitoring of ALK-positive non-small cell lung cancer by copy number profiling combined with targeted sequencing of cell-free DNA. EBioMedicine 62:103103, 2020


Further resources:

Tumoren mittels Blutprobe auf der Spur:

Methods for ctDNA detection and analysis:


Cooperations: Thoraxklinik Heidelberg; Dept. of Pathology at Heidelberg University Medical Center

Support: German Federal Ministry for Education and Research (BMBF) in the funding programs German Centers for Lung Research (DZL),


Prostate Cancer Genomics and Transcriptomics


In the framework of the International Cancer Genome Consortium (ICGC), we have contributed to the molecular risk classification of tumors (prostate, lung, and PCAWG) using (epi) genomic and transcriptomic characterization of tissue samples.
The successful finalization of the ICGC project "The Genomes of Early Onset Prostate Cancers" funded by the BMBF (ICGC-EOPC) led to a comprehensive integrated data set of molecular patterns in young patients: The characterization of 292 prostate cancer (PrCa) genomes revealed age-related genomic alterations and clock-like APOBEC-driven mutational processes contributing to the earliest mutations in PrCa patients. By integrating DNA methylation and RNA expression data from tumors diagnosed with early-onset PrCa, we identified four robust subgroups that readily stratified patients into high- and low-risk groups. We combined our cohort of early-onset patients and identified risk-stratification groups to develop a framework to predict the temporal and clinical outcome order of somatic alterations.


Selected publications:

• Bauer S, Ratz L, Heckmann-Nötzel D, Kaczorowski A, Hohenfellner M, Altevogt P, Kristiansen G, Duensing S, Klauck SM, Sültmann H. miR-449a repression leads to activated NOTCH signaling in TMPRSS2:ERG fusion positive prostate cancer cells. Cancers 13(5), 964, 2021
• Angeles AK, Heckmann D, Flosdorf N, Duensing S, Sültmann H. The ERG-regulated LINC00920 promotes prostate cancer cell survival via the 14-3-3ε- FOXO pathway. Molecular Cancer Research 18(10):1545-1559, 2020
• The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578(7793), 82-93, 2020
• Gerhäuser C, Favero F, Risch T, Simon R, Feuerbach L, Assenov Y, Heckmann D, (...), Sültmann H, Brors B, Plass C, Yaspo ML, Korbel JO, Schlomm T, Weischenfeldt J. Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories. Cancer Cell 34(6):996-1011, 2018


Cooperations: Depts. of Urology and Molecular Urooncology at Heidelberg University Medical Center; Div. of Biostatistics, DKFZ

Support: German Federal Ministry for Education and Research (BMBF), International Cancer Genome Consortium (ICGC)



Genomics of Diseases


Our genomics expertise is utilized in cooperative projects aiming at the analysis of genes and biological processes in diverse diseases. For example, we have contributed to the characterization of spatial and molecular heterogeneity of renal cell cancers, to the investigation of viral sequences in cancer genomes, and to the identification of the receptor for Hepatitis B viruses entering mammalian cells.

Selected Publications:

  • Zapatka M, Borozan I, Brewer, DS, Iskar M, Grundhoff A, Alawi M, Desai N, Sültmann H, Moch H, PCAWG Pathogens Working Group, ICGC/TCGA Pan-cancer Analysis of Whole Genomes Network, Cooper CS, Eils R, Ferretti V, Lichter P. The landscape of viral associations in human cancer. Nature Genetics 52(3):320-330, 2020
  • Christopoulos P#, Dietz S#, Kirchner M, Volckmar AL, Endris V, Neumann O, Ogrodnik S, Heussel CP, Herth FJ, Eichhorn M, Meister M, Budczies J, Allgäuer M, Leichsenring J, Zemojtel T, Bischoff H, Schirmacher P, Thomas M, Sültmann H*, Stenzinger A*. Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival. Cancers, 11, 124, 2019
  • Zhang Z, Filzmayer C, Ni Y, Sültmann H, Mutz P, Hiet M-S, Vondran FWR, Bartenschlager R, Urban S. Hepatitis D Virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes. J Hepatol 69(1):25-35, 2018
  • Dietz S, Sültmann H, Du Y, Reisinger E, Riediger AL, Volckmar AL, Stenzinger A, Schlesner M, Jäger D, Hohenfellner M, Duensing S, Grüllich C, Pahernik S. Patient-specific molecular alterations are associated with metastatic clear cell renal cell cancer progressing under tyrosine kinase inhibitor therapy. Oncotarget 8(43):74049-74057, 2017
  • Hoefflin R, Lahrmann B, Warsow G, Hübschmann D, Spath C, Walter B, Chen X, Hofer L, Macher-Goeppinger S, Tolstov Y, Korzeniewski N, Duensing A, Grüllich C, Jäger D, Perner S, Schönberg G, Nyarangi-Dix J, Isaac S, Hatiboglu G, Teber D, Hadaschik B, Pahernik S, Roth W, Eils R, Schlesner M, Sültmann H, Hohenfellner M, Grabe N, Duensing S. Spatial niche formation but not malignant progression is a driving force for intratumoral heterogeneity. Nat Commun 7:ncomms11845, 2016

Cooperations: Depts. of Urology and Molecular Urooncology at Heidelberg University Medical Center; Div. of Molecular Genetics, DKFZ Heidelberg; Hepatitis B Research Group, Heidelberg University

Support: DKFZ intramural funding; German Federal Ministry for Education and Research (BMBF) in the German Cancer Consortium (DKTK).

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