Linda D. Siracusa, PhD
Bluemle Life Sciences Building, Room 719
Philadelphia, PA 19107-5541
(215) 923-4153 fax
Most Recent Peer-reviewed Publications
- Collagen content in skin and internal organs of the Tight Skin mouse: An animal model of scleroderma
- Identification of five novel modifier loci of Apc Min harbored in the BXH14 recombinant inbred strain
- The armadillo repeat domain of Apc suppresses intestinal tumorigenesis
- A Tcf4-GFP reporter mouse model for monitoring effects of Apc mutations during intestinal tumorigenesis
- Cancer-associated genomic regions (CAGRs) and noncoding RNAs: Bioinformatics and therapeutic implications
BSc, Cornell University, Ithaca, NY
PhD, State University of New York at Buffalo, Roswell Park Cancer Institute, Buffalo, NY
Frederick Cancer Research and Development Center, Frederick MD
Postdoctoral Fellow and Scientist Associate with Dr. Neal Copeland and Dr. Nancy Jenkins
Research & Clinical Interest
The power of genetics coupled with screening genomes of individual mammals is leading to discovery of genes conferring susceptibility or resistance to cancer. My laboratory uses molecular biology, classical genetics, and bioinformatics to study genes that influence the biology of the gastrointestinal tract and the development of cancer. The system we chose involves the tumor suppressor gene Adenomatous Polyposis Coli (APC). Mutations in the Adenomatous Polyposis Coli (APC) gene are responsible for most inherited and sporadic colorectal cancers. ApcMin mice have a mutation in the murine homologue of the human APC gene and develop multiple adenomas along their intestinal tract. Quantitative trait locus (QTL) studies identified the Modifier of Min 1 (Mom1) locus on mouse chromosome 4 that dramatically lowers ApcMin-adenoma number and size. We found that the secretory type II Phospholipase A2 (Pla2g2a) gene is responsible for the Mom1 phenotype. We also discovered the spontaneous Mom2 mutation that lowers small intestine adenoma numbers and colon adenoma incidence. A mutation in the ATP synthase (Atp5a1) gene is responsible for the Mom2 phenotype. Tumor suppression studies indicate a novel mechanism of cellular lethality that is specific to the tumor lineage and involves a distinct genetic pathway. Further work is ongoing to understand the full effects of Mom1 and Mom2 on tumorigenesis. All of this research is performed in collaboration with the laboratory of Dr. Arthur M. Buchberg.
We completed large-scale backcrosses and identified several novel modifier loci. Congenic lines are established and evaluated for tumor phenotypes. Gene expression analyses and bioinformatics tools help prioritize genes for further study and determine which pathways are prime candidates for conferring tumor resistance. Comprehensive examination of these modifier loci in human cancers will facilitate an understanding of their role in tumor initiation, growth, and progression. Further studies will lead to insights of modifier genes as biomarkers for cancer risk assessment, prevention, diagnosis, and their predictive value for response to treatment.
We also hypothesized that microRNAs can be tumor susceptibility genes. To this end, we established a database comparing the positions of mouse microRNAs across the genome with the positions of loci conferring susceptibility to eight different solid tumors. Statistical analyses revealed a highly significant association between the presence of microRNA genes and the locations of tumor susceptibility loci. Comparisons of the sequence of microRNAs between inbred strains that are known to differ in their resistance or susceptibility to specific types of tumors has revealed polymorphisms, primarily in the regions upstream of the microRNA stem-loop structure. Studies are continuing to assess microRNA expression in the gastrointestinal tract, in both normal and disease states.
The comprehensive examination of novel modifier loci in human tumors will facilitate an understanding of the relationship between the effects of modifier genes on tumor initiation, growth, and progression. The abundance of mouse mutants provides a wealth of heritable alterations useful for defining the molecular basis of tumor phenotypes. Further investigations will lead to insights regarding the role of modifier genes in cancer risk assessment, tumor prevention, diagnosis, and their predictive value for response to treatment.