Molecular Changes Associated with PCa bone metastases

Summary

Principal Investigator: Kenneth Pienta
Abstract: In the RFA for Molecular interaction between tumor cells and bone, one area of emphasis was that "A comprehensive analysis of genetic changes occurring between primary tumor and bone metastases and the development of a tractable system to study bone metastases are needed." This application focuses on this area of emphasis by demonstrating that we have developed a method for comprehensive genetic expression analysis between both primary prostate cancer and metastatic prostate cancer but also between prostate cancer metastases that develop in bone versus soft tissue sites. This analysis has allowed us to preliminarily identify potential genes of importance that regulate prostate cancer metastasis to bone. We hypothesize that we can identify genetic changes that are important in prostate cancer metastasis to bone and determine their functional significance in prostate cancer bone metastasis. To test this hypothesis we have developed the following specific aims: Specific Aim 1: Characterize the expression signature of prostate metastases derived from bone versus soft tissue sites. Utilizing tissue acquired through our Rapid Autopsy Program, we will identify genes that are differentially expressed in prostate cancer metastases at the gene and tissue level. Specific Aim 1A: We will utilize tissue derived from multiple bone versus soft tissue sites from a variety of patients (variable genetic background). Specific Aim 1B: We will utilize tissue derived from multiple bone and soft tissue sites from a single patient (common genetic background). Specific Aim 1C: Utilize prostate cancer cell lines grown on bone matrix versus liver extracellular matrix to look at differential gene expression. Specific Aim 2: We will investigate the function of differentially expressed genes between bone and soft tissue metastases to determine their significance to prostate cancer metastasis to bone. We will start with the FROUNT/PERICENTRIN gene, identified in our preliminary experiments. Specific Aim 2A: We will study the potential significance of genes that are differentially expressed between bone and soft tissue metastases as prognostic and diagnostic markers for prostate cancer utilizing our tissue microarrays with the corresponding clinical follow-up data. In summary, we have developed an effective paradigm for identifying and characterizing genes whose expression is altered in metastatic versus primary prostate cancers. By concentrating on genetic changes between bone and soft tissue metastases, a better understanding of the molecular biology that underpins prostate cancer metastasis should be elucidated. This knowledge could lead to the development of better biomarkers of disease progression as well as targets for therapy.
Funding Period: 2003-09-24 - 2007-08-31
more information: NIH RePORT

Top Publications

  1. pmc Characterization of bone metastases from rapid autopsies of prostate cancer patients
    Rohit Mehra
    Department of Internal Medicine and Urology, University of Michigan Medical School, 7303 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
    Clin Cancer Res 17:3924-32. 2011
  2. ncbi ETS gene aberrations in atypical cribriform lesions of the prostate: Implications for the distinction between intraductal carcinoma of the prostate and cribriform high-grade prostatic intraepithelial neoplasia
    Bo Han
    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, USA
    Am J Surg Pathol 34:478-85. 2010
  3. ncbi A polycomb repression signature in metastatic prostate cancer predicts cancer outcome
    Jindan Yu
    Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Cancer Res 67:10657-63. 2007
  4. ncbi Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer
    Beth E Helgeson
    Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 0602, USA
    Cancer Res 68:73-80. 2008
  5. pmc A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer
    Bharathi Laxman
    Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 0602, USA
    Cancer Res 68:645-9. 2008
  6. pmc Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer
    Rohit Mehra
    Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Cancer Res 68:3584-90. 2008
  7. pmc A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer
    Bo Han
    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
    Cancer Res 68:7629-37. 2008
  8. pmc Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression
    Bo Han
    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
    Mod Pathol 22:1083-93. 2009
  9. pmc Characterization of ETS gene aberrations in select histologic variants of prostate carcinoma
    Bo Han
    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Mod Pathol 22:1176-85. 2009
  10. ncbi Integrative analysis of genomic aberrations associated with prostate cancer progression
    Jung H Kim
    Michigan Center for Translational Pathology, Department of Pathology, Department of Urology, Program of Bioinformatics, and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109 0940, USA
    Cancer Res 67:8229-39. 2007

Scientific Experts

  • Kenneth Pienta
  • Robert D Loberg
  • B T Chen
  • Robert G Abbott
  • Rohit Mehra
  • Arul M Chinnaiyan
  • Scott A Tomlins
  • Bo Han
  • Rajal B Shah
  • Lei Wang
  • Xuhong Cao
  • Robert J Lonigro
  • Nallasivam Palanisamy
  • Bharathi Laxman
  • Jianjun Yu
  • Javed Siddiqui
  • Khalid Suleman
  • Chandan Kumar-Sinha
  • Anjana Menon
  • Sooryanarayana Varambally
  • Saravana M Dhanasekaran
  • Jindan Yu
  • Mark A Rubin
  • Sunita Shankar
  • Ming Zhou
  • Beth E Helgeson
  • John T Wei
  • James E Montie
  • Jung H Kim
  • Daniel R Rhodes
  • Debashis Ghosh
  • Russel S Taichman
  • Robert Axelrod
  • Xiaojun Jing
  • David C Smith
  • Neena E Philips
  • Linda Sercia
  • Cristina Magi-Galluzzi
  • Katherine A Linetzky
  • Nishi Singhal
  • Nameeta Shah
  • Yusong Gong
  • Jie Cao
  • John R Prensner
  • Alex Tsodikov
  • Qi Cao
  • Nirmish Singla
  • Xiaosong Wang
  • David S Morris
  • Wenjuan Gu
  • Atreya Dash
  • Xiaoju Wang
  • Kerby Shedden
  • Shanker Kalyana-Sundaram
  • Guoan Chen
  • David E Axelrod

Detail Information

Publications20

  1. pmc Characterization of bone metastases from rapid autopsies of prostate cancer patients
    Rohit Mehra
    Department of Internal Medicine and Urology, University of Michigan Medical School, 7303 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
    Clin Cancer Res 17:3924-32. 2011
    ..No intensive studies, however, have been conducted on osseous metastatic tissues from patients with metastatic prostate cancer due to lack of access to such tissues for profiling and other research...
  2. ncbi ETS gene aberrations in atypical cribriform lesions of the prostate: Implications for the distinction between intraductal carcinoma of the prostate and cribriform high-grade prostatic intraepithelial neoplasia
    Bo Han
    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, USA
    Am J Surg Pathol 34:478-85. 2010
    ..However, there are lesions that do not fully satisfy the criteria for IDC-P yet are worse than typical HGPIN and are difficult to distinguish based on morphologic criteria alone...
  3. ncbi A polycomb repression signature in metastatic prostate cancer predicts cancer outcome
    Jindan Yu
    Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Cancer Res 67:10657-63. 2007
    ..Therefore, PcG proteins play a central role in the epigenetic silencing of target genes and functionally link stem cells, metastasis, and cancer survival...
  4. ncbi Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer
    Beth E Helgeson
    Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 0602, USA
    Cancer Res 68:73-80. 2008
    ..Together, our results suggest that the family of 5' partners previously identified in ETV1 gene fusions can fuse with other ETS family members, suggesting numerous rare gene fusion permutations in prostate cancer...
  5. pmc A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer
    Bharathi Laxman
    Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 0602, USA
    Cancer Res 68:645-9. 2008
    ..8% and 60.8%, respectively. Taken together, these results provide the framework for the development of highly optimized, multiplex urine biomarker tests for more accurate detection of prostate cancer...
  6. pmc Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer
    Rohit Mehra
    Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Cancer Res 68:3584-90. 2008
    ..These findings suggest that TMPRSS2-ERG with Edel is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease...
  7. pmc A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer
    Bo Han
    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
    Cancer Res 68:7629-37. 2008
    ..Fourth, we identified a ubiquitously expressed, androgen-insensitive gene, DDX5, fused in frame with ETV4, leading to the expression of a DDX5-ETV4 fusion protein...
  8. pmc Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression
    Bo Han
    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
    Mod Pathol 22:1083-93. 2009
    ..PTEN deletion and ERG rearrangement may cooperate, but contribute at different stages, in prostate cancer progression...
  9. pmc Characterization of ETS gene aberrations in select histologic variants of prostate carcinoma
    Bo Han
    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Mod Pathol 22:1176-85. 2009
    ..Overall, our data provide insight into the origin, molecular mechanism, and phenotypic association of ETS fusions in histologic variants of prostate carcinoma...
  10. ncbi Integrative analysis of genomic aberrations associated with prostate cancer progression
    Jung H Kim
    Michigan Center for Translational Pathology, Department of Pathology, Department of Urology, Program of Bioinformatics, and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109 0940, USA
    Cancer Res 67:8229-39. 2007
    ..Integrative analysis with matched mRNA profiles identified genetic alterations in several proposed candidate genes implicated in prostate cancer progression...
  11. pmc The evolving biology and treatment of prostate cancer
    Russel S Taichman
    University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA
    J Clin Invest 117:2351-61. 2007
    ..As the population ages and prostate cancer prevalence increases, challenges remain in the diagnosis of clinically relevant prostate cancer as well as the management of the metastatic and androgen-independent metastatic disease states...
  12. ncbi A paradigm for the treatment of prostate cancer bone metastases based on an understanding of tumor cell-microenvironment interactions
    Robert D Loberg
    Department of Urology, University of Michigan Urology Center, The University of Michigan, Ann Arbor, Michigan 48109 0946, USA
    J Cell Biochem 96:439-46. 2005
    ..They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics...
  13. ncbi The "emigration, migration, and immigration"of prostate cancer
    Kenneth J Pienta
    University of Michigan Urology Center, Ann Arbor, MI 48109 0946, USA
    Clin Prostate Cancer 4:24-30. 2005
    ..This review describes the steps of metastasis using a paradigm of emigration to migration to immigration, with prostate cancer as a model system...
  14. ncbi Advances in prostate cancer chemotherapy: a new era begins
    Kenneth J Pienta
    Michigan Urology Center, University of Michigan, Ann Arbor, MI, USA
    CA Cancer J Clin 55:300-18; quiz 323-5. 2005
    ..Building on these advances, several new traditional chemotherapeutic agents as well as new targeted therapies are under development...
  15. ncbi Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype
    Robert D Loberg
    University of Michigan, Ann Arbor, MI, USA
    J Clin Oncol 23:8232-41. 2005
    ..Here, we review the current therapeutic strategies for targeting the prostate cancer-bone microenvironment and several single- and multiagent targeted approaches to the treatment of advanced prostate cancer that are under development...
  16. pmc Evolution of cooperation among tumor cells
    Robert Axelrod
    Gerald R Ford School of Public Policy and Department of Political Science, University of Michigan, Ann Arbor, MI 48109, USA
    Proc Natl Acad Sci U S A 103:13474-9. 2006
    ..Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches...
  17. ncbi Simulating the hallmarks of cancer
    Robert G Abbott
    Sandia National Laboratories, P O Box 5800, Albuquerque, NM 87185, USA
    Artif Life 12:617-34. 2006
    ..CancerSim enables a modeler to study the dynamics of a developing tumor and simulate how progression can be altered by tuning model parameters...
  18. ncbi Integrative molecular concept modeling of prostate cancer progression
    Scott A Tomlins
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
    Nat Genet 39:41-51. 2007
    ..Taken together, these data show that analyzing gene expression signatures in the context of a compendium of molecular concepts is useful in understanding cancer biology...
  19. ncbi The lethal phenotype of cancer: the molecular basis of death due to malignancy
    Robert D Loberg
    Internal Medicine and Urology, University of Michigan, Ann Arbor, MI, USA
    CA Cancer J Clin 57:225-41. 2007
    ....
  20. ncbi Preliminary study of immunomagnetic quantification of circulating tumor cells in patients with advanced disease
    B T Chen
    Department of Urology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
    Urology 65:616-21. 2005
    ....