1. Research Background

It is well established that most cells can switch between several functional states. Prominent examples for this are immune cells during activation, epithelial cells after wounding, liver cells when regenerating or detoxifying, or tumour cells reacting to growth signals as well as nutrient availability. All of these cues significantly change these cells’ behaviour and their metabolism.

More recently, however, it has become evident that the relationship between signalling cues and metabolism is not a one-way street. While it is often the case that a stimulus, for example a mitogenic factor, induces a cellular behaviour, in this case growth, and that this cellular reprogramming encompasses a metabolic adaptation, a growing body of data, including ours, shows that affecting metabolic pathways alone, can also induce well defined, predictable, and directional cellular behaviours, without the need of an initiating signalling based stimulus. This redefines metabolism as not merely an adaptation to accommodate energetic and synthetic needs of cells in a given functional state, but as an actual driver of cellular behaviour.

2. Research questions addressed by the group:

In our lab, we are interested in connecting metabolism to cellular function and thus explain tissue organisation in health and disease. To achieve our goal we need to understand metabolism at single cell resolution, we thus utilise high resolution mass spectrometric imaging, a technology that allows us to measure thousands of metabolites in situ directly on tissue sections.

Currently, we are particularly interested in the B class of vitamins, all of which act as co-factors in key metabolic reactions and thus sit at the switch-points between different metabolic pathways. We have been able to show that oversupplying Vitamin B_5, the precursor of Coenzyme A, changes metabolic fluxes and by doing so reprogrammes cells into a new functional state. Conversely, we could also show that failure of adopting such metabolic states, for example by Vitamin B₅ withdrawal,  precludes the exertion of the matching cellular programme even after a signalling stimulus has been received. We thus observe necessity and sufficiency with regards to metabolism and cell function. We have shown these phenomena in varied model systems including breast cancer cells, primary, and immortalised T cells, and immortalised hepatocytes.

Ultimately, having these deep insights will help us to understand how derailed metabolism in diseases such as cancer and ageing leads to aberrant cell function and disease progression.

3. Possible project(s):

1) Metastatic clone tracing and metabolism

It is well established that during tumour progression, clones that acquire metastatic potential require significant metabolic flexibility to grow in the distinct environment of their metastatic target site. It is not clear, if these metabolic trats were present and genetically encoded in the original heterogeneous tumour population, or if these are dynamic adaptation that happen during metastatic spread. We will thus use a recently published technology termed CATCH, that allows to trace back metastatic clones to a heterogenous cell population prior to metastatic spread. We will use this technology, to detect clones with metastatic potential to several different organs, and subsequently analyse these clones via mass spectrometric imaging, to assess if they show distinct metabolic traits even before metastasising.

2) Metabolic Compartmentalisation and Immune cell function

Cytotoxic T cells, fully reprogramme their metabolism after activation, to accommodate activities such as rapid proliferation, and massive cytokine production. To date, it remains poorly understood how this reprogramming is achieved at a molecular level, particular with respect to intracellular routing of metabolism into different cellular compartments. We aim to unravel the subcellular fluxes of metabolites during T cell activation with the goal of 1) understanding if failure of proper routing affects T cell activity in age and 2) if affecting these fluxes can be used in a curative fashion to design better therapeutic T cells.

4. Applied Methods and model organisms:

Methods: Mass Spectrometric imaging, including data analysis; bulk and spatial metabolomics; primary T cell generation and manipulation; cell culture; all standard molecular biological methods, multiplexed antibody-based stainings, various cancer models.

Organisms: Mainly mice.

5. Desirable skills and qualifications:

Extensive wet-lab experience, some knowledge of metabolomics, animal work, basic coding skills.

6. References and key publications:

Kreuzaler, P. et al. Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer. Nat Metab 5, 1870–1886 (2023).

Kreuzaler, P. et al. Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling. Proc. Natl. Acad. Sci. U. S. A.116, 22399–22408 (2019).

Kern, C. et al. Orbi‐SIMS mediated metabolomics analysis of pathogenic tissue up to cellular resolution. Chemistry Methods4, (2024).

Umkehrer, C. et al. Isolating live cell clones from barcoded populations using CRISPRa-inducible reporters. Nat. Biotechnol.39, 174–178 (2021).