Vilma Yuzbasiyan-Gurkan, Ph.D.

Research

Investigations in Dr. Yuzbasiyan-Gurkan's laboratory focus on 1)
understanding the molecular genetics of cancer and cancer stem cells; 2)
utilizing the isolated gene pools of purebred dogs to map and identify
cancer susceptibility and other genetic disease loci and  3) translating
the molecular findings to useful prognostic tools and therapeutic
targets. Spontaneously occurring cancers in animals constitute both
important clinical challenges as well as models for understanding basic
cancer biology and can aid greatly in the evaluation of new treatment
modalities.

Work from the laboratory in the recent years has identified a series of
activating mutations in c-KIT in canine and feline mast cell tumors and
has shown their prognostic significance. Further work has identified the
role of activating mutations in c-KIT in other spontaneous canine
tumors, specifically gastrointestinal stromal tumors (GISTs). Mutations
identified in the companion animals overlap with those observed in
humans in both mastocytosis and in GIST patients. However, there are
some that are unique in each species.  The group has generated
expression constructs of each mutant as well as the wildtype gene and is
testing the ability of each isoform to transform normal fibroblasts in
both human and canine primary cell lines. Preliminary result indicate
that ectopic expression of the several of the isoforms are able to
transform the cell lines, expand their lifespan and result in cells that
are able to form colonies in soft agar, grow in low serum. Other aspects
of their tumorigenic phenotype in vitro and in vivo are being assessed,
as well as changes in critical downstream signaling events.  In addition
to providing insights into tumorigenesis, this system will allow the
evaluation of the effect of different tyrosine kinase inhibitors on
cells expressing different isoforms and will allow for preclinical
evaluation of such drugs and facilitate personalization of each
treatment regiment for both the human and the companion animal patient.

Another major effort in the lab is focused on understanding the critical
events in tumorigenis in canine and human osteosarcomas. To this end,
the laboratory is studying in both spontaneously occurring osteosarcomas
in dogs and humans as well as generating model systems of tumorigenesis,
manipulating specific genes in mesenchymal stem cells (MSCs) and in
their differentiating progeny. The group has developed methods for the
isolation of MSC from bone and adipose tissue in both humans and dogs.
Regulatable expression constructs containing various oncogenes have been
generated and transduced into these MSCs, and studies of their effect of
tumorigenesis is ongoing- with some very enticing preliminary results
that indicate that the timing of the oncogene expression in the
differentiation stage of the cell is critical to the tumorigenic
phenotype.  In parallel studies, different fractions of osteosarcoma
cell lines are being evaluated for being the fraction of cells that are
capable of repopulating the tumor, i.e. for constituting the cancer stem
cell population.  In all of these studies, the aim is both to understand
the tumorigenic process and to identify critical targets for effective
treatment that can be translated to the dog and the human patient.

A long-standing interest has been the study of familial clusters of
cancer in dogs, which may be critical in identifying novel tumor
suppressor genes and/or providing insights into cancer biology.  A major
focus is on Bernese Mountain Dogs that present with various cancers,
including osteosarcomas, mast cell tumors, lymphomas and malignant
histiocytic sarcomas. The laboratory has established a DNA and tumor
repository of index cases and DNA from immediate relatives, along with
detailed phenotylaunch genome wide association, transcriptome, including microRNA,
profiling and other molecular studies utilizing these samples. A recent
partnership has been established with TGEN and Van Andel Research
Institute to utilize their XenoBase propriety software to identify
critical targets bsed on such analysis.  In addition, variation in the
cytochrome p450 (CYP) genes in dog is being evaluated to determine
genotype effects on drug metabolism.