Dr. Stefano Casola

Dr. Stefano Casola

Beneficiary (B5)

At age 24, Casola graduated from the Faculty of Medicine at the University Federico II of Naples. He had one goal in mind: understanding cancer. This drive led him in 1997 to the Institute of Genetics, University of Cologne, Germany where he worked at the forefront under the mentorship of prominent immunologist Klaus Rajewsky. Here he began studying the molecular mechanisms controlling B-cell function during a protective immune response and the genetic alterations promoting the occurrence of B-cell tumors called lymphomas. The research together proved fruitful as Casola and his colleagues explored and explained how the Epstein Barr Virus, the causative agent of infectious mononucleosis can contribute to the occurrence of aggressive B-cell lymphomas including Hodgkin's lymphoma. Continuing at his alma mater he obtained his PhD in Cellular and Molecular Biology and Pathology in 1999.

In 2001, Casola followed dr. Rajewksy to Boston working at the Harvard Medical School. During this time, Casola became Junior investigator at the CBR Institute of Biomedical Research and Instructor at the Department of Pathology, Havard Medical School.

In 2006, Casola decided to return to Europe and accepted the offer to become a group leader at Milan's IFOM. Today, with the same ambition and dedication of his university days, Stefano Casola and his team studies how B-lymphocytes protect our organism from foreign pathogens, what promotes B-cell transformation into malignant lymphomas and new therapeutic strategies for the cure of these blood cancers.

 

Our group has three long-term goals:

  • To dissect at the molecular level the key events that guide the transition of B cells through the sequential stages of the GC reaction. For this purpose, a series of conditional mouse mutant strains in which deletion of genes coding for a defined set of transcription factors, signaling proteins, surface receptors and chromatin remodeling enzymes will be specifically induced in GC B cells. The role of these factors in the control of GC B cell survival, selection and terminal differentiation will be determined. Also, their involvement in regulating Ig somatic mutation and class-switch recombination will be investigated. A similar approach will be followed to dissect the role of a defined set of microRNAs in GC B cell responses.
  • To identify key genetic determinants controlling GC B-cell lymphoma initiation, maintenance and progression. Using existing mouse models of different subtypes of non-Hodgkin B cell lymphomas, we will delete in a conditional manner in lymphoma cells, at different stages of tumorigenesis, genes thought to play a critical role in (GC) B cell survival, proliferation and differentiation. The latter approach will be complemented by studies in which primary lymphoma cells of the different tumor subtypes will be transplanted into syngeneic recipient after infection with a library of lentiviral vectors expressing in an inducible manner short interfering RNAs directed against genes (initially B-cell specific) controlling specific functions of GC B cells. A major effort will be given to study the role of the BCR and its downstream signaling mediators in tumor B cell survival/proliferation. The final goal of these studies is to identify new therapeutic targets for the treatment of the different forms of GC B-cell malignancies.
  • Tumor initiation, maintenance and progression results from functional cooperation between two or more oncogenes, often associated with loss of tumor suppressor gene activity. In this context, our group aims to identify partners of oncogenes whose function is commonly deregulated in specific forms of non-Hodgkin lymphomas including BL, FL and DLBCL. For this purpose, in mouse models of non-Hodgkin B cell lymphomas expressing the dominant oncogene as a transgene, insertional mutagenesis will be specifically induced in GC B cells. Acceleration of lymphoma onset in lymphoma-prone mice will confirm functional cooperation between oncogenes, eventually associated with loss of tumor suppressor gene function. The genes cooperating with the "primary" oncogene to accelerate disease will be cloned with PCR-based methods from genomic DNA extracted from a series of independent primary lymphomas. The biological relevance of the newly identified gene products will be validated analyzing their expression andactivation status in a series of primary human lymphoma specimens representative of the different types of non-Hodgkin B cell lymphomas. A similar approach will be attempted to identify oncogenic partners of the Epstein Barr Virus (EBV)-encoded proteins LMP1 and LMP2A expressed in the Hodgkin-Reed Sternberg tumor cells of EBV+ cases of classical Hodgkin lymphoma. For this purpose we will use mice, available in the lab, which express the viral proteins in a conditional manner.

B-cell lymphoma
Immunology
Germinal Center
Mouse models

 

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