Kathleen Kelly Siebenlist, 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.
We use two complementary approaches, genetically engineered mouse models (GEMMs) and xenograft models, to address mechanistic questions concerning the origin of PC metastasis, metastatic colonization of secondary organs, and therapeutic responses. Many significant questions concerning PC are approachable with mouse models. Some advantages of GEMMs 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. A strength of the laboratory is our ability to employ a wide variety of in vivo models and imaging modalities.
We have focused upon two models, both of which represent highly frequent genetic aberrations observed in human prostate cancer. The first is an aggressive PC model that initiates from deletion in prostate epithelium of the tumor suppressors, Pten and TP53. The goals of this project are to characterize the cellular and molecular phenotypes of Pten/TP53 null, castration sensitive and resistant, tumor-propagating populations and to apply the knowledge gained toward analyzing mechanisms of human prostate cancer progression and castration resistance. Our characterization of the Pb-Cre4; Ptenfl/fl, TP53fl/fl model revealed that the amplification and plasticity of PC progenitor cells contributes to the lethal, aggressive nature of Pten/TP53 null PC. Recent findings have identified PTEN deletion and AR pathway crosstalk as significant in human and mouse castration-resistant PC (CRPC) development. We have combined castration of tumor-bearing mice with FACS-based fractionation to assay and molecularly characterize tumor propagating cell fractions. We currently are identifying and analyzing mechanisms of Pten-loss dependent survival.
The second project uses a unique model that we developed, which recapitulates the most common mutation in PC, translocation of the ERG transcription factor locus behind the TMPRSS2 promoter. TMPRSS2-ERG (T-E) translocations occur in about 50% of clinically identified prostate cancers. Although T-E translocations are believed to occur early in tumorigenesis, their role in transformation is not known. T-E translocations are not transforming alone but collaborate with additional mutations. In order to model the natural expression of T-E, we produced transgenic lines containing a recombinant bacterial artificial chromosome (BAC) with an extended TMPRSS2 promoter driving genomic ERG. The use of the natural TMPRSS2 promoter has allowed us to investigate novel aspects of T-E regulation and expression. We have found that T-E is expressed in heterogeneous prostate epithelial cell populations, including progenitor-like populations where T-E expression correlates with increased clonogenicity, and that T-E is expressed in a subpopulation of castration-resistant cells. Our goal is to determine the mechanistic, functional effects of combining mutations that are commonly found in T-E translocation positive prostate cancers. Our approach combines de novo tumorigenesis in GEM models with the use of pre-neoplastic epithelial cell cultures to analyze specific characteristics of transformation.
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
This page was last updated on June 15th, 2017