Important questions matter

“If I had an hour to solve a problem I'd spend 55 minutes thinking about the problem and five minutes thinking about solutions”… Albert Einstein 

What we like to do:

The overarching goal of our laboratory is to discover how the signaling system controlled by the heme molecule regulates the life of the cells and intact organisms. We aim to explore its relationship with oxidative stress, and to dissect the role of this molecular axis in the mechanisms driving cancer formation and evolution.

 

While heme has been known for decades as an indispensable prosthetic group which allowed the development of aerobic life, more recent discoveries have demonstrated that heme exists also as an exchangeable molecule, capable of transmitting “messages” by dynamically and reversibly binding to proteins. The results of these pioneering studies brought to light novel functions of heme and showed that the heme “message or signal’’ orchestrates diverse and fundamental biological processes in a great variety of organisms throughout all kingdoms of life. 

 

Our group recently discovered an unprecedented molecular mechanism allowing the heme-oxidative stress axis to regulate the activity of an E3 ubiquitin ligase to control the degradation of a heme-sensor transcription factor. We revealed how genetic mutations of this pathway in lung cancer patients critically sustain tumor progression.

Propelled by our curiosity, today’s research in our lab proceeds towards unexplored directions, which may lead us to understand fundamental mechanisms of cell biology and to design new strategies to advance cancer therapeutics.

 

Our main research avenues are:

1. To uncover how the heme-oxidative stress pathway controls protein degradation via the Ubiquitin-Proteasome System

2. To understand how the heme-oxidative stress pathway regulates gene expression by modulating the activity of intracellular transcriptional sensors

3. To unravel the mechanisms linking alteration of the heme-oxidative stress pathway to lung tumor development and progression

 

Tools and Methodologies:

To address these questions, we use multidisciplinary approaches that leverage biochemical and molecular biology tools, together with proteomics and mouse genetics:

  • We use biochemistry, cell, and molecular biology (e.g., WB, IP, PCR, qPCR, IF/IHC, confocal microscopy) to investigate at the amino acidic level the details of protein-protein interaction (PPI) and to dissect the mechanisms of protein-protein cross-regulation. 

  • Our lab implements mass spectrometry-based interactomic (e.g., GC-MS) analyses to reveal complex protein networks beyond individual PPI. 

  • We employ a wide range of high-throughput techniques to study the proteome and the transcriptome of the cells, including TMT-based whole proteome profiling, RNAseq and single cell RNAseq transcriptomic profiling.

  • We have set up several in vitro cellular models, both normal and tumor cells, to understand the impact of the pathways we examine on cell biology as well as on the tumorigenic features of the cancer cells.

  • We take advantage of different in vivo tumor models: (i) xenografts mouse models, to quickly analyze the results of our genetic and pharmacological approaches on tumor growth and dissemination; (ii) genetically engineered mouse models in combination with CRISPR/Cas9 editing systems, to elucidate the effects of our genetic manipulations on tumor development and progression.