In our lab, we focus on the role of protocadherins
in brain development and pathology.
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The cadherin superfamily, a group of calcium-dependent cell adhesion molecules, is believed to be essential for central nervous system development.
Patients with epilepsy (EPI) frequently exhibit co-occurring cognitive and behavioural issues associated with autism spectrum disorder (ASD) and intellectual disability (ID). Notably, up to 90% of children with ASD and ID present neurological alterations closely linked to an earlier onset of EPI. Emerging evidence suggests that cell adhesion molecules (CAMs) play a crucial role in neurodevelopment, regulating synaptic connectivity and neuronal communication. Dysregulation of CAMs has been implicated in both epilepsy and neurodevelopmental disorders, yet how early epileptic events influence CAM function and contribute to ASD and ID severity remains unclear.
Protocadherins are emerging as promising candidates in the pathologies associated with autism spectrum disorder and epilepsy.
Protocadherins (PCDHs), a subfamily of the cadherin superfamily, are essential for neurodevelopment, contributing to neuronal differentiation, synapse formation, and the establishment of neural circuit specificity. Dysregulation of PCDHs has been linked to various neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, and epilepsy, highlighting their role in brain connectivity and function. However, the specific functions of PCDHs in these disorders remain poorly understood, underscoring the need for further research to elucidate their precise mechanisms.
Protocadherins are increasingly recognised for their role in brain cancer, where they influence tumour progression, metastasis, and the regulation of cell-cell adhesion in cancerous tissues.
PCDHs have gained attention for their involvement in brain cancer, where they play a significant role in tumour progression and malignancy. These calcium-dependent cell adhesion molecules are crucial for maintaining cell-cell interactions and neural tissue integrity, and their dysregulation can contribute to tumorigenesis. In brain cancer, altered expression of specific PCDHs can affect cell adhesion, migration, and invasion, promoting metastasis and poor prognosis. Some PCDHs may act as tumour suppressors, while others might facilitate cancer cell survival and proliferation. Understanding the precise mechanisms by which PCDHs influence brain cancer could lead to new therapeutic strategies targeting these molecules to improve treatment outcomes.
We aim to provide answers to two questions:
What is the etiology behind Pcdhs-associated ASD and epilepsy?
What is the role of Pcdhs in brain cancer development and progression?
Dr Andrzej Cwetsch
Masters degree
During my master's studies, I worked on stem cell differentiation in Dr. Osyczka’s laboratory at Jagiellonian University, Poland. During this time, I completed my first internship at the Italian Institute of Technology (IIT) in Italy, where I had the opportunity to work with Dr. Laura Cancedda on seizure susceptibility in rodent models. This experience was my first exposure to experimental neuroscience and played a crucial role in shaping my scientific interests. Shortly after completing my master's, I moved to Italy—initially as an intern and later as a Ph.D. student under Dr. Cancedda's supervision.
PhD
My Ph.D. thesis performed in Dr. Laura Cancedda's lab at the Italian Institute of Technology focused on the role of Protocadherin 19 (Pcdh19) in the rat brain in the context of Epileptic Encephalopathy, Early Infantile, 9 (EIEE9). For the first time, I was able to demonstrate that the mosaic expression of Pcdh19 in excitatory pyramidal neurons leads to morphological deficits accompanied by behavioral impairments characteristic of EIEE9. In addition to my thesis work, I contributed to developing a patent and protocol for 3-electrode IUE. An interdisciplinary approach combining technical and neurodevelopmental research has always been central to my work and remains a key aspect of my future plans.
Postdoc
To further explore the role of Pcdhs in the earliest stages of brain development, I continued my postdoctoral research in Dr. Alessandra Pierani’s lab at the Imagine Institute in Paris, a leading expert in Cajal-Retzius cells (CRs). Supported by two foundation grants, my research focused on the transcription factor Dbx1 and its role in regulating cell fate through Pcdhs. To deepen this investigation, I was awarded a prestigious EMBO short-term fellowship to work in Dr. Malumbres’ lab at the Spanish National Cancer Research Centre in Madrid, where I further examined Dbx1’s influence on cell cycle.
Leader
My research group is particularly interested in the involvement of Pcdhs in multiple processes, i.e., in cortex and hippocampus formation, activation of adult neural stem cells, and neuronal cell cycle.
Now, thanks to the Valencian Government's Talented Researcher Support Programme, I began my career as an independent researcher in 2021 within the prof. Isabel Fariñas Lab.
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