Developmental Cancer Genomics

Halbritter Group

We study aberrant development in pediatric cancers using computational genomics. We aim to achieve a mechanistic understanding of the underlying biology to inspire diagnostics and treatments.

Florian Halbritter
Background

Cancer is a disastrous growth of cells in the body. In the most common types of cancer, this growth is brought on by a series of many mutations – accumulated throughout life and possibly influence by extrinsic factors.
Childhood cancers are different. In young age, cells have not usually attained many mutations yet, but rather there are individual catastrophic events that occur in undifferentiated cells during the orderly growth of the organism. These singular mutations throw developing cells of their designated path and result in malignancies. However, for most pediatric cancers, the exact histogenesis is not fully understood. Insight into how mutations affect development will ultimately elucidate new avenues for detecting (diagnosis), projecting (prognosis), and interfering (therapy) with aberrant development in childhood cancers.

Our research

Taking apart pediatric cancer bit by bit

We are a team of computational biologists approaching childhood cancer development with a scientist’s curiosity in three facets:

Charting and modelling (cancer) cell development

In our research, we contribute to charting the molecular changes that occur in cells during organismal development and to juxtapose those to the biology of tumors. For instance, we have profiled the transcriptome and epigenome of developing hematopoietic progenitors (see figure). Aberrant hematopoiesis is the root of the most common childhood malignancies (leukemia), but also of the rare myeloid neoplasm Langerhans cell histiocytosis (LCH). With the lab of Caroline Hutter (at CCRI), we investigated intra-tumor heterogeneity in LCH at single-cell level (see figure) and uncovered an unexpected cellular hierarchy between multiple coexisting LCH cell states. In our ongoing work, we reach out beyond hematopoietic malignancies to study pediatric sarcomas and blastomas.

Stem-cell-based models
When do cancerous cells diverge from normal development? What are the gene-regulatory mechanisms that define these cell states and govern plasticity? To answer this sort of question, we have in recent years turned toward stem-cell-based in vitro models to study the very root of oncogenic transformation. For this purpose, we seek out and work with experts for stem cell technologies at CCRI and around the world. Together, we use the culture models as analytically tractable systems to identify the precise effects of oncogenic events on differentiating cells. Ultimately, we hope that this knowledge may help to inspire new diagnostic and therapeutic approaches in the management of childhood cancers.



High-throughput genomics and computational biology

Our research benefits heavily from technological breakthroughs in the field of functional genomics. We now routinely use high-throughput functional genomics assays (including single-cell RNA-seq, ATAC-seq, ChIP-seq, RRBS/WGBS, lineage tracing) and, more recently, spatially resolved techniques to pair cell-intrinsic states with cell-extrinsic influences. Armed with these powerful technologies, we generate rich, multi-faceted portrays of cells, which we dissect using bioinformatic pipelines combined with statistical analysis and machine learning.

Algorithms for data analysis

To advance our field, we develop algorithms for data analysis (e.g., bioinformatics workflows), we pair up with experimental research groups to test, optimize, and customize assays (e.g., we evaluated DNA methylation biomarker assays and helped to develop a massively parallel reporter assay), and we commit to open science practices by regularly sharing data, code, and resources with the community.

Links

Projects and Funding
  • Comprehensive cell contact tracing (C3T)
    CCRI responsible Principal Investigator: Florian Halbritter
    Additional CCRI Principal Investigator: Martin Distel
    Grant from the Austrian Science Fund (FWF), TAI-1000 Ideas Program, ID – TAI 454
    Duration: 01/09/2021 to 31/12/2022
  • Tracking Ewing sarcoma origin by developmental and trans-species genomics (ORIGIN)
    CCRI responsible Principal Investigators and Coordinator: Heinrich Kovar
    Additional CCRI Principal Investigators: Martin Distel, Florian Halbritter
    Alex´s Lemonade Stand Foundation (ALSF), Crazy 8 Initiative Award Program
    Duration: 01/03/2021 to 28/02/2025
Selected Articles

Agerer B*, Koblischke M*, Gudipati V*, Montaño-Gutierrez LF, Smyth M, Popa A, Genger JW, Endler L, Florian DM, Mühlgrabner V, Graninger M, Aberle SW, Husa AM, Shaw LE, Lercher A, Gattinger P, Torralba-Gombau R, Trapin D, Penz T, et al. SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses. Sci Immunol. 2021;6(57). https://doi.org/10.1126/sciimmunol.abg6461, * shared first authorship

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#. Epigenomics and single-cell sequencing define a developmental hierarchy in langerhans cell histiocytosis. Cancer Discov. 2019;9(10):1406-1421. https://doi.org/10.1158/2159-8290.CD-19-0138, * shared first authorship, # shared senior authorship

Barakat TS*, Halbritter F*, Zhang M, Rendeiro AF, Perenthaler E, Bock C, Chambers I. Functional Dissection of the Enhancer Repertoire in Human Embryonic Stem Cells. Cell Stem Cell. 2018;23(2):276-288. https://doi.org/10.1016/j.stem.2018.06.014, * shared first authorship

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#. Specification of tissue-resident macrophages during organogenesis. Science (80- ). 2016;353(6304):aaf4238. https://doi.org/10.1126/science.aaf4238, * shared first authorship, # shared senior authorship

Farlik M*, Halbritter F*, Müller F*, Choudry FA, Ebert P, Klughammer J, Farrow S, Santoro A, Ciaurro V, Mathur A, Uppal R, Stunnenberg HG, Ouwehand WH, Laurenti E, Lengauer T, Frontini M#, Bock C#. DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation. Cell Stem Cell. 2016;19(6):808-822. https://doi.org/10.1016/j.stem.2016.10.019, * shared first authorship, # shared senior authorship

Collaborating Partners

National: Igor Adameyko (MUW), Christoph Bock (CeMM), Christa Buecker (MFPL), Matthias Farlik (MUW), Johannes Gojo (MUW), Cornelia Kasper (BOKU), Martin Leeb (MFPL), Daniela Lötsch-Gojo (MUW), Florian Grebien (VetMed), Julia Ressler (MUW). InternationalStefan Barakat (Erasmus MC, NL), Keisuke Kaji (Edinburgh, UK), Minoru Takasato (JP), Anestis Tsakiridis (Sheffield, UK)

About Florian Halbritter

Dr. Florian Halbritter (PhD) studied Cognitive Science at the University of Osnabrück. In 2008 he entered a PhD program in Stem Cell Bioinformatics under the supervision of Simon Tomlinson and Ian Chambers at the MRC Centre for Regenerative Medicine of the University of Edinburgh. After graduating in 2012 he worked as a postdoc at the University of Edinburgh before moving to the laboratory of Christoph Bock at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in 2015. He joined St. Anna Children’s Cancer Research Institute (CCRI) as a Principal Investigator in 2018. As a computational biologist, Florian Halbritter studied the epigenome of stem cells, immune cells, and cancer using functional genomics technologies. He developed and applied data analysis methods and analyzed thousands of genomics datasets.

Team

Florian Halbritter
Principal Investigator
Christoph Hafemeister
Postdoctoral Fellow
Luis Fernando Montaño-Gutierrez
Postdoctoral Fellow
Maud Plaschka
Postdoctoral Fellow
Mohamed Shoeb
PhD Student
Sara Wernig-Zorc
Postdoc