Guardavaccaro lab

Previous work in our lab uncovered crosstalk between ubiquitylation and phosphorylation that regulates cell growth and proliferation. We further showed that deregulation of these mechanisms plays a central role in tumorigenesis. We are now expanding our efforts to understand how signaling networks control fundamental cellular processes and how their dysregulation contributes to human disease. In particular, we are pursuing the following research lines:

Signaling networks that guide cell fate decisions in development and disease

The development and maintenance of multicellular organisms depend on precisely regulated cell fate decisions. These decisions determine whether a cell proliferates, differentiates, or undergoes programmed cell death, and errors in these processes can lead to developmental disorders, cancer, and other diseases. Cell fate decisions are orchestrated by complex signaling networks that integrate extracellular cues with intracellular regulatory mechanisms.

Our laboratory is interested in understanding how these signaling networks are dynamically regulated to ensure robust and context-dependent cell fate outcomes. In particular, we focus on the role of the ubiquitin system as a key modulator of signaling pathways. Ubiquitylation regulates the stability, localization, and activity of numerous signaling components, thereby influencing the strength, duration, and specificity of cellular responses.

By combining in vitro and in vivo models (Danio rerio) as well as organoids, miniaturized, simplified and self-organized 3D organs, generated by pluripotent stem cells, that mimic their corresponding organs in vivo, we aim to uncover how ubiquitin-dependent regulation controls signaling networks during normal development and how its dysregulation contributes to disease. Ultimately, our work seeks to provide insights into the principles governing cell fate decisions and to identify new molecular targets for therapeutic intervention.

Molecular mechanisms in normal cells and cancer

Cells rely on finely tuned molecular mechanisms to maintain tissue structure, function, and adaptability throughout development and adult life. These mechanisms regulate key aspects of cellular behavior, including polarity, adhesion, movement, and interactions with the surrounding environment. In healthy tissues, their coordinated activity ensures proper organization and controlled responses to physiological cues.

In cancer, these regulatory systems become disrupted. Alterations in signaling and structural pathways can drive abnormal cellular behavior, enabling increased plasticity, invasion, and disease progression. Understanding how molecular mechanisms operate in normal cells, and how their dysregulation contributes to cancer, is central to identifying new points of intervention.

We study the molecular pathways that govern cellular behavior under physiological conditions and investigate how their aberrant regulation promotes cancer development and progression. By uncovering these mechanisms, we aim to advance fundamental biological understanding and lay the groundwork for strategies with potential translational impact.

Spatially restricted substrate degradation

Although the ubiquitin-proteasome system is known to control substrate degradation in all cellular compartments, substrate proteolysis at specific membrane compartments is not well understood. We study how substrate degradation is spatially restricted at specific membrane compartments and characterize the molecular mechanisms regulating recruitment and activation of ubiquitin ligases locally at cellular membranes. Moreover, we investigate the role of ubiquitylation in the dynamic remodeling of the ER. The importance of maintaining proper ER architecture is underscored by the evidence that mutations in proteins involved in ER formation and maintenance are responsible for the primary pathological defects of the neurological disorder hereditary spastic paraplegia.

Zebrafish

We use zebrafish (Danio rerio) for disease modelling, target identification, and drug screening in collaboration with the Sangfelt lab (Karolinska Institutet) and the Vettori lab (UniVR). The reasons for this choice are manifold: high fecundity, low-cost maintenance, high conservation of pathways driving cancer, as well as optical transparency, which makes the zebrafish particularly well-suited for imaging tumor development, metastasis, and microenvironmental interactions. In addition, zebrafish are an excellent model for drug screens due to the ease with which drugs can be administered to embryos in their water.

Targeted Protein Degradation

We use Targeted Protein Degradation (TPD) strategies to selectively eliminate proteins of interest by harnessing the cell's endogenous degradation machinery. Rather than inhibiting protein activity, TPD induces protein removal, enabling durable and precise modulation of protein function. Our work includes small-molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs), which recruit E3 ubiquitin ligases to target proteins, as well as Molecular Glue Degraders (MGDs) that promote or stabilize target–ligase interactions. Together, these approaches offer powerful opportunities to interrogate protein function and to target disease-relevant proteins that are difficult to address with traditional inhibitors.