Kathleen Kelly, Ph.D.
Laboratory of Genitourinary Cancer Pathogenesis
Building 37, Room 1068
Bethesda, MD 20892
Our laboratory focuses on understanding the mechanistic consequences of specific genetic alterations that lead to the development of prostate cancer (PC), especially as related to progression. 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. Our goal is to improve detection and treatment of prostate cancer through understanding genomic and biochemical mechanisms of disease progression.
We use two complementary approaches, patient-derived xenografts/organoids and genetically engineered mouse models (GEMMs). A strength of our laboratory is our ability to employ a wide variety of in vivo models and imaging modalities. We use the large cohort of LuCaP patient-derived CRPC xenografts established by our collaborators at the University of Washington. The LuCaP cohort represents the genotypic and phenotypic heterogeneity of advanced prostate cancer clinical samples. To facilitate experimental manipulations, including genetic modifications and high throughput screening assays, we optimized organoid methods for establishing and maintaining in vitro cultures of LuCaP xenograft tumor cells. In addition to the LuCaP organoids, we also have developed a number of organoid cultures from NIH clinical center CRPC patient biopsy samples. Together these organoid cultures in combination with matching PDX tumors provide an extensive, clinically-relevant experimental platform. One major effort is focused upon high throughput screens to determine therapeutic sensitivity and metabolic characteristics (including imaging tools) as they relate to molecular characteristics. A second effort addresses the genetic and epigenetic mechanisms of CRPC dedifferentiation and neuroendocrine transdifferentiation that occurs in response to androgen deprivation.
GEMMs are particularly useful for the availability of genetically-defined tumor tissue, the ability to longitudinally investigate various stages of prostate cancer progression, and the ease of manipulating the hormone environment. Models of aggressive CRPC in mice have provided insight into poorly differentiated tumors enriched for cancer stem/progenitor cells. Combined PTEN/TP53 mutations occur in ~30% of clinical CRPC. Our characterization of a Pten/Tp53 null prostate cancer GEMM model revealed that the amplification and plasticity of luminal prostate cancer progenitor cells contributes to the aggressive and castration resistant nature of the disease. Ongoing investigations are focused upon the signaling pathways that promote self-renewing cancer stem cells and their relationship to castration indifference.
Agarwal S, Hynes PG, Tillman HS, Lake R, Abou-Kheir WG, Fang L, Casey OM, Ameri AH, Martin PL, Yin JJ, Iaquinta PJ, Karthaus WR, Clevers HC, Sawyers CL, Kelly K. Identification of Different Classes of Luminal Progenitor Cells within Prostate Tumors. Cell Rep. 2015;13(10):2147-58.
Ward Y, Lake R, Martin PL, Killian K, Salerno P, Wang T, Meltzer P, Merino M, Cheng SY, Santoro M, Garcia-Rostan G, Kelly K. CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model. Oncogene. 2013;32(22):2726-38.
Liu YN, Abou-Kheir W, Yin JJ, Fang L, Hynes P, Casey O, Hu D, Wan Y, Seng V, Sheppard-Tillman H, Martin P, Kelly K. Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition. Mol Cell Biol. 2012;32(5):941-53.
Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K. LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells. Cancer Res. 2011;71(23):7301-11.
Martin P, Liu YN, Pierce R, Abou-Kheir W, Casey O, Seng V, Camacho D, Simpson RM, Kelly K. Prostate epithelial Pten/TP53 loss leads to transformation of multipotential progenitors and epithelial to mesenchymal transition. Am J Pathol. 2011;179(1):422-35.
Related Scientific Focus Areas
Genetics and Genomics
This page was last updated on April 17th, 2019