Guardavaccaro lab

Previous work in our lab has uncovered crosstalk mechanisms between ubiquitylation and phosphorylation regulating cell growth and proliferation. We also investigated how deregulation of these mechanisms plays a central role in tumorigenesis. Currently, we are interested in expanding our knowledge of how signaling networks control fundamental cellular processes and how their alterations result in human disease. In particular, we are pursuing the following research lines:

Signaling networks that guide cell fate decisions in development and disease

Cell fate decisions are strictly controlled by a variety of regulatory mechanisms. We are seeking to understand how signaling networks underlying cell fate decisions are influenced by the ubiquitin system. To that aim, we are utilizing in vitro and in vivo models as well as organoids, miniaturized, simplified and self-organized 3D organs, generated by pluripotent stem cells, that mimic their corresponding organs in vivo.

Molecular mechanisms regulating epithelial cell migration

Epithelial cell migration is crucial for the development and regeneration of epithelial tissues. In this process, epithelial cells lose cell-cell adhesion, develop a mesenchymal cell polarity and, eventually, acquire a highly motile phenotype that enables the invasion of surrounding tissues. Aberrant regulation of epithelial cell migration has a major role in pathological processes such as the development of cancer metastasis and tissue fibrosis. We are studying the molecular mechanisms controlling epithelial cell migration and eventually develop strategies that may have clinical potential.

Molecular mechanisms underlying 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 suited to image tumor development, metastasis, and microenvironmental interactions. In addition, zebrafish is an excellent model for drug screens due to the ease with which drugs can be administered to embryos in their water.

PROTAC degraders

We also utilize PROteolysis TArgeting Chimeras (PROTACs) as small molecule tools to induce the proteasomal degradation of specific proteins in the cell. PROTACs are bivalent protein degraders composed of two protein-binding molecules connected by a linker. One molecule binds to a ubiquitin ligase and the other interacts with a target protein meant for degradation. The concurrent interaction of the PROTAC with the E3 and the target protein triggers ubiquitylation of the latter and its subsequent degradation by the proteasome. PROTACs have shown therapeutic promise in targeting disease-causing proteins – particularly those considered undruggable with traditional small molecule inhibitors - and are emerging as a new concept in precision medicine and drug discovery.