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Michael B. Aregger, Ph.D.

Michael Aregger, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
Molecular Targets Program

RESEARCH SUMMARY

Michael Aregger’s research focuses on how cancer cells rewire gene expression and metabolism in order to adapt to changing environmental conditions. Towards this, he has developed CRISPR-Cas based screening technologies that afford the systematic perturbation of multiple genes and genetic segments and that can be coupled with various phenotypic readouts. Dr. Aregger’s laboratory applies those genome engineering tools and functional genomics approaches in order to reveal genetic interactions and cancer dependencies, and to identify regulators of metabolic plasticity in cancer cells.

Areas of Expertise

1) genetic interactions 2) cancer metabolism 3) gene regulation 4) CRISPR-Cas 5) genome engineering 6) functional genomics

Research

A major goal of biomedical research is to reveal genetic dependencies and cellular processes cancer cells rely on in order to exploit them therapeutically. The development of CRISPR-based genome editing technologies have opened the door for efficient perturbation of mammalian genomes and, as such, provide powerful tools for exploring genotype-to-phenotype relationships. Importantly, the combination of CRISPR technology with functional genomics approaches can be harnessed to systematically identify genetic dependencies and cancer vulnerabilities across diverse cell lines and growth conditions. Michael Aregger’s research aims to expand our understanding of how cancer cells dynamically regulate gene expression and cellular metabolism in response to changing environmental conditions, and to use this knowledge to identify genetic liabilities that may present novel targets for combinatorial cancer therapeutic approaches.

1. Studying adaptation to metabolic stress

A common feature of many cancers is the reprogramming of cellular metabolism in order to fuel tumorigenesis. Importantly, this rewiring is highly plastic allowing cancer cells to adapt to various tumor microenvironmental stress conditions. In our lab we apply cutting-edge functional genomics methodologies along with transcriptomics, proteomics and focused biochemical approaches to investigate how metabolic plasticity is regulated and what genetic vulnerabilities arise in cancer cells in response to various environmental stress conditions.

2. Identification of context-dependent fitness genes across genetic and environmental backgrounds

In order to identify genes whose function underlie cell proliferation and survival we have developed various CRISPR-based screening technologies for the systematic knockout of genes in human cells. Our genome-wide CRISPR-Cas9 screens expanded the set of human fitness genes and revealed distinct genetic signatures that can be used to predict differential drug response of cancer cells. In our lab we are using similar CRISPR screening approaches to uncover genetic vulnerabilities in cancer cells and study how different environmental conditions influence dependencies on certain cellular pathways.

Figure 1:  Application of CRISPER screens for the detection of core- and context-dependent fitness genes in human cells.

3. Mapping of genetic interaction networks

Genetic interactions occur when mutations in two or more genes result in a phenotype that deviates from the predicted combinatorial effect of perturbing those genes. The mapping of such genetic interactions can provide profound insights into the functional wiring and plasticity of cells, predict novel gene functions, and highlight critical genetic dependencies that may be exploited therapeutically to treat diseases such as cancer.

Using co-isogenic cell lines we interrogated the genetic interaction landscape of lipid metabolism. Our work shed light on the mechanistic basis for cellular adaption to loss of de novo fatty acid synthesis and uncovered a previously uncharacterized gene as a novel regulator of exogenous lipid uptake, demonstrating the power of systematic genetic interaction mapping for functionally annotating the genome.

Figure 2: Genetic interaction mapping using co-isogenic cell lines.

To expand our tools to map genetic interactions we developped CHyMErA (Cas Hybrid for Multiplexed Editing and Screening Applications), a CRISPR-based combinatorial screening platform for the perturbation of multiple genes. CHyMErA is based on the co-expression of Cas9 and Cas12a nucleases in conjunction with a hybrid guide RNA (hgRNA) engineered by the fusion of Cas9 and Cas12a guides and expressed from a single U6 promoter. We have applied CHyMErA for the dual-targeting of single genes, the mapping of genetic interactions between paralogs, and for exon-resolution functional genomics in mammalian cells. In our lab we continue exploring CHyMErA as a powerful tool to uncover genetic interactions and dependencies between various cellular pathways.

Figure 3: CHyMErA combinatorial genome editing platform and examples of its application.

4. Technology development for systematic functional genomics approaches

We have a strong interest in developing and applying cutting-edge CRISPR-based technologies and continue exploring various Cas modalities and effector domains for our screening applications. Furthermore, we are also expanding the readouts for our screening platforms in order to assess genetic dependencies across more information-rich phenotypes.

Available Positions

The Aregger group is looking for enthusiastic lab members who wish to explore genetic interactions and metabolic dependencies in cancer cells. We currently have openings for Postdoctoral Fellows. If you are interested in our work, please send your C.V., a short statement of research interests and contact details of 2-3 references to michael.aregger@nih.gov.

NIH Scientific Focus Areas
Cancer Biology
Genetics and Genomics
Molecular Biology and Biochemistry

Publications

Selected Publications

Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism.

Aregger M, Lawson KA, Billmann M, Costanzo M, Tong AHY, Chan K, Rahman M, Brown KR, Ross C, Usaj M, Nedyalkova L, Sizova O, Habsid A, Pawling J, Lin ZY, Abdouni H, Wong CJ, Weiss A, Mero P, Dennis JW, Gingras AC, Myers CL, Andrews BJ, Boone C, Moffat J.
Nature Metabolism. 2(6): 499-513, 2020.
Full-Text Article
[ Journal Article ]

Genetic interaction mapping and exon-resolution functional genomics with a hybrid Cas9-Cas12a platform

Gonatopoulos-Pournatzis T, Aregger M, Brown KR, Farhangmehr S, Braunschweig U, Ward HN, Ha KCH, Weiss A, Billmann M, Durbic T, Myers CL, Blencowe BJ, Moffat J.
Nature Biotechnology. 38(5): 638-648, 2020.
Full-Text Article
[ Journal Article ]

High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities

Hart T, Chandrashekhar M, Aregger M, Steinhart Z, Brown KR, MacLeod G, Mis M, Zimmermann M, Fradet-Turcotte A, Sun S, Mero P, Dirks P, Sidhu S, Roth FP, Rissland OS, Durocher D, Angers S, Moffat J.
Cell. 163(6): 1515-26, 2015.
Full-Text Article
[ Journal Article ]

CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription

Aregger M, Kaskar A, Varshney D, Fernandez-Sanchez ME, Inesta-Vaquera FA, Weidlich S, Cowling VH.
Molecular Cell. 61(5): 734-746, 2016.
Full-Text Article
[ Journal Article ]

Job Vacancies

Position Degree Required Contact Name Contact Email
Post-doctoral Fellow - Functional genomics, cancer metabolism Ph.D. or equivalent Michael Aregger michael.aregger@nih.gov