High-throughput biology of cancer and immunity

Work Desk

We use multi-omics profiling and CRISPR technology to discover exciting new biology in cancer and immunity, and we take the most interesting results forward, together with our clinical partners to make them useful for precision medicine.

The biological concept of cellular identity connects a cell’s past with its future potential. Our research is based on the hypothesis that epigenetic cell states and the “epigenetic landscape” constitute a highly informative intermediate layer of information processing – one that captures a cell’s regulatory identity and retains the flexibility to respond swiftly to a broad range of perturbations. This definition of the “epigenetic landscape” is not restricted to specific epigenetic marks such as DNA methylation and histone modifications. Rather, it reflects the full range of transcription regulation by which cells translate various inputs into sustainable changes in their cell state. In particular, the epigenetic landscape not only defines a cell’s current state, but also details its developmental past (e.g., cell-of-origin in cancer) and future trajectories (e.g., plasticity in response to drug treatment).

To study the fundamental role of epigenetic and transcription-regulatory programs in cancer and immunity, we have established high-throughput pipelines to profile gene expression (i.e., bulk and single-cell RNA-seq) and transcriptional regulation (e.g., ATAC-seq, RRBS, ChIPmentation) to dissect the epigenetic landscape in patient cohorts and in disease-relevant mouse models. For example, we have established genome-scale maps of tumor heterogeneity in cancers of children (Ewing sarcoma, Langerhans histiocytosis) and elderly patients (glioblastoma, chronic lymphocytic leukemia). Our work also focuses on immune gene regulation – the first single-cell DNA methylation maps of hematopoietic stem cell differentiation and the first systematic map of immune regulation in non-immune cells (“structural immunity”).

Publications

Structural cells are key regulators of organ-specific immune response

Structural cells are key regulators of organ-specific immune response

Krausgruber T*, Fortelny N*, Fife-Gernedl V, Senekowitsch M, Schuster LC, Nemc A, Schmidl C, Rendeiro AF, Lercher A, Bergthaler A, Bock C

Nature  583, 296-302 (2020). DOI: 10.1038/s41586-020-2424-4

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Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia

Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia

Rendeiro AF*, Krausgruber T*, Fortelny N, Zhao F, Penz T, Farlik M, Schuster LC, Kuchler A, Tasnády S, Réti M, Zoltán M, Alpar D*, Bödör C*, Schmidl C*, Bock C*

Nature Communications  11, 577 (2020). DOI: 10.1038/s41467-019-14081-6

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Epigenomics and single-cell sequencing define a developmental hierarchy in Langerhans cell histiocytosis

Epigenomics and single-cell sequencing define a developmental hierarchy in Langerhans cell histiocytosis

Halbritter F*, Farlik M*, Schwentner R, Jug G, Fortelny N, Schnöller T, Pisa H, Schuster LC, Reinprecht A, Czech T, Gojo J, Holter W, Minkov M, Bauer WM, Simonitsch-Klupp I, Bock C*, Hutter C*

Cancer Discovery  9, 1406-1421 (2019). DOI: 10.1158/2159-8290.CD-19-0138

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Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL

Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL

Schmidl C*, Vladimer GI*, Rendeiro AF*, Schnabl S*, Krausgruber T, Taubert C, Krall N, Pemovska T, Araghi M, Snijder B, Hubmann R, Ringler A, Runggatscher K, Demirtas D, de la Fuente OL, Hilgarth M, Skrabs C, Porpaczy E, Gruber M, Hoermann G, Kubicek S, Staber PB, Shehata M*, Superti-Furga G*, Jäger U*, Bock C*

Nature Chemical Biology  15, 232-240 (2019). DOI: 10.1038/s41589-018-0205-2

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The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

Klughammer J*, Kiesel B*, Roetzer T, Fortelny N, Nemc A, Nenning KH, Furtner J, Sheffield NC, Datlinger P, Peter N, Nowosielski M, Augustin M, Mischkulnig M, Strobel T, Alpar D, Ergüner B, Senekowitsch M, Moser P, Freyschlag CF, Kerschbaumer J, Thomé C, Grams AE, Stockhammer G, Kitzwoegerer M, Oberndorfer S, Marhold F, Weis S, Trenkler J, Buchroithner J, Pichler J, Haybaeck J, Krassnig S, Mahdy Ali K, von Campe G, Payer F, Sherif C, Preiser J, Hauser T, Winkler PA, Kleindienst W, Wurtz F, Brandner-Kokalj T, Stultschnig M, Schweiger S, Dieckmann K, Preusser M, Langs G, Baumann B, Knosp E, Widhalm G, Marosi C, Hainfellner JA, Woehrer A*, Bock C*

Nature Medicine  24, 1611-1624 (2018). DOI: 10.1038/s41591-018-0156-x

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DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma

DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma

Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schönegger A, Schuster M, Hadler J, Surdez D, Guillemot D, Lapouble E, Freneaux P, Champigneulle J, Bouvier R, Walder D, Ambros IM, Hutter C, Sorz E, Amaral AT, de Alava E, Schallmoser K, Strunk D, Rinner B, Liegl-Atzwanger B, Huppertz B, Leithner A, de Pinieux G, Terrier P, Laurence V, Michon J, Ladenstein R, Holter W, Windhager R, Dirksen U, Ambros PF, Delattre O, Kovar H, Bock C*, Tomazou EM*

Nature Medicine  23, 386-395 (2017). DOI: 10.1038/nm.4273

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Specification of tissue-resident macrophages during organogenesis

Specification of tissue-resident macrophages during organogenesis

Mass E*, Ballesteros I*, Farlik M*, Halbritter F*, Günther P, Crozet L, Jacome-Galarza CE, Händler K, Klughammer J, Kobayashi Y, Gomez-Perdiguero E, Schultze JL, Beyer M*, Bock C*, Geissmann F*

Science  353, 6304 (2016). DOI: 10.1126/science.aaf4238

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Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks

Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks

Rendeiro AF*, Schmidl C*, Strefford JC*, Walewska R, Davis Z, Farlik M, Oscier D, Bock C*

Nature Communications  7, 11938 (2016). DOI: 10.1038/ncomms11938

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* shared first or shared senior authorship