Several projects are ongoing aimed to study the contribution of genomic instability in the form of whole chromosome aneuploidies, single-nucleotide variants (SNVs) and small insertions and deletions (INDELs) to early transformation and progression to tumorigenesis. The area of expertise of the laboratory is molecular cytogenetics, and we apply customized fluorescent in situ Hybridization (FISH) assays to study aneuploidy and other forms of DNA damage in single cells. More recently we expanded our arsenal of tools to include single cell genomic assays based on next generation sequencing.
Genomic instability is a hallmark of cancer and it is induced by a host of risk factors. Age for example, is the biggest single risk factor for cancer and genome instability has long been implicated as the main causal factor of aging. The molecular mechanisms by which increased genomic instability leads to increased cancer risk with age remains unknown and this is an active area of investigation in the laboratory.
We uncovered unexpectedly high levels of age-related accumulation of whole chromosome aneuploidy in the aging brain. We showed that aneuploidy is sufficient to induce senescence, a permanent cell cycle often accompanied by a senescence associated secretory phenotype (SASP) which can have deleterious effects on the surrounding microenvironment. Using single cell genomic analysis of postmortem human brain tissues our current work aims to define the cells and the brain areas in which genomic instability arise during aging and study how this process increase cancer risk. These experiments combined with in culture 3D cortical spheroids and murine models in which the fate of aneuploid astrocytes and other brain cell types can be traced are expected to define the contribution of aneuploidy to disease and establish the molecular pathways altered in the presence of aneuploid cells.
Inherited germline mutations in the BRCA1 or BRCA2 genes cause premature aging phenotypes and greatly increase the risk of breast and ovarian cancer, presumably as consequence of deficient DNA repair, by elevating somatic mutational errors. However, this has never been directly demonstrated through a comprehensive analysis of the somatic mutational landscape of primary, non-cancer, mammary epithelial cells of women diagnosed with pathogenic BRCA1 or BRCA2 germline mutations. Likewise, the tissue specificity of BRCA1 and BRCA2 penetrance and the molecular mechanisms by which some modifiers increase tumor risk in mutation carriers remains largely unknow. Using single cell genomic analyses combined with custom Fluorescent in situ Hybridization (FISH) assays and 3D mammospheres established from mastectomies of mutation carriers and controls we aim to define the genomic landscape of primary germline mutant cells in response to modifiers of penetrance. Projects are ongoing to define the role of hormonal exposure on mutation rate and to study the evolution of clones with a genetic makeup like those observed in breast tumor cells. A similar project directed to study the molecular mechanisms of progression to high-grade serous carcinomas in the ovary of the putative precursor lesion serous tubal intraepithelial carcinoma (STIC) in the fallopian tubes is also ongoing.
Incoming students will be able to carve thesis dissertation projects in the above defined areas of interest using human primary 3D culture assays and or in vivo murine models of human disease. Students interested in applying and or developing analytical tools to the type of data generated in the lab are also welcomed.
I am strongly dedicated to mentorship and I am committed to providing mentees with a challenging intellectual environment and solid training in molecular genetics with a translational focus. I am actively involved in mentorship of PhD candidates and postdoctoral trainees. I have long standing history of mentorship, from undergraduate students (10), PhD students (5), postdoctoral trainees (6), clinical fellows (12) and junior faculties with clinical background (2), as well as robust record in obtaining funding.
I have recently relocated my laboratory to the Rutgers Cancer Institute of New Jersey (CINJ) and I am enthusiastic to expand my group and my mentorship role within the microbiology and molecular genetics programs.
