Trainee Spotlight: Rossella Tricarico, PhD
Dr. Alfonso Bellacosa’s lab
Fox Chase Cancer Center
When I was an undergraduate student at the University of Bari in Italy, the molecular characterization of the Philadelphia chromosome was the first experiment I worked on. I would never have thought that almost a decade later, I would have the opportunity to work at Fox Chase Cancer Center, where the Philadelphia chromosome was co-discovered!
When I was younger, I had a passion for ballet dancing and was fascinated by the mystery of human body. However, when I discovered the beauty of science during a genetics course in high school, I decided to leave ballet behind, and instead become a scientist. I started my journey as an undergraduate student in Dr. Mariano Rocchi’s lab at the University of Bari where I gained experience in tumor molecular cytogenetics and bioinformatics. After attaining a degree in Biological Science, I enrolled as a post-graduate in the Laboratory of Medical Genetics School at the University of Florence. Later I joined Dr. Maurizio Genuardi’s lab for my PhD in Molecular Genetics at the Catholic University of Rome, investigating the role of DNA repair genes in genetic predisposition to colorectal cancer. In 2012, my journey led me to join Dr. Alfonso Bellacosa’s lab at Fox Chase Cancer Center, where I continued to explore the genetic susceptibility and molecular mechanisms of cancer and genetic diseases. Currently, I am focusing on the role of two DNA repair enzymes, MBD4 and TDG, in genomic and epigenomic instability. My main interest is in the characterization of the role of MBD4 and TDG in DNA repair and transcriptional regulation in development and cancer. My career goal is to contribute to a collaborative research group focused on the intersection of disease and genomic and epigenomic stability.
MBD4 is a multifunctional protein involved in several cellular processes, including the maintenance of genomic stability by preventing C>T transitions. Our previous work showed that MBD4 is frequently mutated in hereditary and sporadic colorectal cancers (CRCs) characterized by Mismatch Repair (MMR) defects. To-date, however, it is unclear whether MBD4 alterations are only a secondary consequence of genomic instability due to MMR defect, or can contribute to the “mutator phenotype”. We addressed this question by a combined human-mouse study and found that in CRC cases with MBD4 variants, transition mutation frequency was 30-fold higher than in CRC cases without MBD4 or MMR variants, indicating that MBD4 defects may affect the mutational landscape independently of the MMR inactivation. In addition, Mbd4 knockout mice showed reduced survival in a MMR-deficient background. Our data suggest that MBD4 inactivation may contribute to tumorigenesis and act as a modifier of MMR-deficient cancer phenotypes, likely by increasing the genomic instability of a subset of MMR-defective tumors and, more specifically, by contributing to elevated C>T transitions. Our mouse studies also suggest that MBD4 mutations may be responsible for a worse outcome and possibly resistance to therapy of a subset of MMR-deficient tumors.
Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis
Tricarico R, Cortellino S, Riccio A, Jagmohan-Changur S, Van der Klift H, Wijnen J, Turner D, Ventura A, Rovella V, Percesepe A, Lucci-Cordisco E, Radice P, Bertario L, Pedroni M, Ponz de Leon M, Mancuso P, Devarajan K, Cai KQ, Klein-Szanto AJ, Neri G, Møller P, Viel A, Genuardi M, Fodde R, Bellacosa A. Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis. Oncotarget. 2015 Dec 15;6(40):42892-904.