Our Science – Kelly Website

Kathleen Kelly, Ph.D.

Cell and Cancer Biology Branch Branch Chief National Cancer Institute Building 37, Room 1068 37 Convent Drive Bethesda, MD 20892 Phone:   301-435-4651 Fax:   301-435-4655 E-Mail:   kellyka@mail.nih.gov

Biography

Dr. Kelly received her Ph.D. from the University of California, Irvine. She completed her postdoctoral training in the laboratory of Philip Leder, Harvard Medical School, and she has maintained an independent research program at the NCI since 1984. Dr. Kelly's interests have focused on the genetic regulation of cell growth, cancer progression and metastasis.

Research

RESEARCH INTERESTS
The overarching theme of the Kelly Lab is the identification and characterization of signaling pathways that mediate cancer progression and metastasis. Evaluating proximal signaling pathways for their regulation of functions that are required by metastatic cells is a logical approach to selecting therapeutic targets for treatment and prevention of metastasis. A tenet of metastasis research is the principle that different types of cancer have affinity for specific organs, in part based upon a permissive interaction of cells in the tumor with those in the microenvironment. Prostate cancer (PC) is the most frequently diagnosed non-cutaneous cancer in men, and although organ confined PC is highly treatable with surgery and/or radiation, metastatic disease is incurable and leads to significant morbidity and mortality. The focus of our laboratory is metastatic PC. We use two complementary approaches, genetically engineered mouse models (GEMM's) and xenograft models, to address mechanistic questions concerning the origin of PC metastasis, metastatic colonization of secondary organs, and therapeutic responses. A strength of the laboratory is our ability to employ a wide variety of in vivo models and imaging modalities.

PC METASTASIS MODELS
We have used xenograft PC models to investigate signaling pathways that contribute to organ-specific metastatic colonization and to mechanistically validate the utility of a small molecule angiogenesis inhibitor in the treatment of PC bone and brain metastasis. We discovered that the Ras downstream pathway mediated by RalGEF, the Ral Guanine Nucleotide Exchange Factor, leading to RalA and RalB activation plays a necessary role in experimental PC metastasis to bone. Targets of Ral pathway activation that regulate PC cell anchorage-independent growth and PC interactions with cells in the bone microenvironment are under investigation. We have combined xenograft tumor models with a variety of non-invasive imaging techniques to demonstrate a significant response of metastatic PC bone and brain tumors to angiogenesis inhibitors.

Many significant questions concerning PC are approachable with mouse models. Some advantages of GEMM's are the unlimited availability of genetically-defined tumor tissue, the ability to longitudinally investigate various stages of PC progression, and the ability to manipulate the hormone environment. No model exists of prostate adenocarcinoma leading to metastatic disease at a reasonable frequency. We are using a transplantation model of invasive PC initiated by epithelial cell specific deletion of Pten and P53 to 1) investigate the phenotype of PC tumor initiating cells, and 2) investigate cooperating genetic lesions leading to PC metastasis.

CD97 AND CANCER PROGRESSION
Our laboratory also has a long-standing interest in CD97, an adhesion-linked GPCR, which has been implicated in progression of certain cancers, including thyroid and prostate cancers. Adhesion-linked GPCR's form a unique structural sub-family of GPCR's, consisting of a bipartite extracellular adhesive domain noncovalently associated with a conserved GPCR. Relatively little is known about the signaling properties of this interesting GPCR family. Our interest in CD97 stems partly from the fact that GPCR's are highly druggable targets. We have determined that the ligand for CD97 is integrin α5β1 and that one major signaling mechanism is through coupling with a specific heterotrimeric G protein pathway. In addition to investigating CD97-initiated signaling pathways, we have placed much of our effort into analyzing the role of CD97 in invasion and metastasis.

This page was last updated on 8/1/2008.