Ongoing Research Areas

The lab addresses functional and theoretical aspects of the interplay between metabolic regulation and drug treatment, from antimicrobial to anticancer drugs, offering a highly interdisciplinary scientific and training environment.

Here are some of the key questions that drive and inspire the research in our lab:

  1. How does metabolism mediate rapid and long-term adaptation to continuous environmental changes as well as genetic or chemical perturbations?
  2. What are the underlying evolutionary forces that influence how pathogenic bacteria or cancer cells operate metabolism?
  3. How can we pharmacologically interfere with metabolic regulation?
  4. Can we develop computational models capable of predicting cellular responses to drugs that have not yet been tested, or anticipate the functional consequences of genetic mutations?

Metabolic fingerprinting of drug modes of action

An innovative contribution of our experimental and theoretical work is the establishment of a new perspective and methodology to search for new drug modes of action and ways to bypass drug resistance. To this end, we established a unique multiplexed, unbiased framework that, by linking genetic to drug-induced changes in nearly a thousand metabolites, allows for high-throughput functional annotation of compound libraries. The approach consists first of generating a reference map of metabolic changes from genetic interference (e.g. gene knockdown). Next, a new computational strategy (iSim) to compare genetic with small molecule-induced metabolic changes allows making de novo predictions of compound mechanisms of action.

From gene expression changes to rewiring of metabolism

By integrating cross-sectional omics data, we construct global network models across different levels of biological information to investigate the information flow from transcription factors to metabolic pathways and vice versa. Our mission is to develop unique integrative models to (i) disentangle the role of transcriptional and post-translational regulation in mediating adaptation and pathogenicity during bacterial infection or colonization of distal organs by malignant cells and (ii) thereby reveal potential vulnerabilities exploitable for therapeutic treatments.

Dissecting short- and long-term metabolic adaptation to drug treatment

While much progress has been made in systematically mapping the genetic networks of mutations conferring drug resistance, very little is known about the rewiring of metabolism in resistant and/or tolerant mutants and even less about the constraints imposed by metabolism on the evolution of drug resistance and compensatory mechanisms. We aim to: (i) understand the role of metabolism in mediating the early adaptive response of bacteria and cancer cells to small molecules and (ii) investigate the synergy between the natural selection of resistance mutations and the nutrient composition of the environment.

New tools to explore dynamic adaptive responses to endogenous and exogenous perturbations

In recent years, omics technologies (e.g. phospho-proteomics, proteomics, transcriptomics, metabolomics, etc.) have become a special focus in many branches of biology, requiring biologists to apply quantitative methods and theoretical scientists to acquire a deeper understanding of how data were generated. Overall, advancements in high-throughput omics technologies came along with the need for new tools to analyze and interpret the large amount of generated data. We are working to find new ways of integrating large datasets that span different time domains and many regulatory layers. The development of integrated and innovative computational, and experimental systems-level approaches plays an essential role in our mission to understand the decision-making process of cells upon drug treatment.