Although most prostate cancer deaths are due to metastasis, our understanding of the biological and molecular mechanisms underlying metastatic prostate cancer is still limited. Our proposed research is focused on elucidating molecular mechanisms involved in tumor progression, dissemination, and metastasis of prostate cancer using analyses of in vivo mouse models to inform on human prostate cancer. Thus, we have generated genetically-engineered mouse (GEM) models of metastatic prostate cancer. Using lineage-tracing of these models, we have defined a temporal progression from tumorigenesis to metastasis, and have isolated primary tumor, disseminated, and metastatic cells for molecular analyses. In parallel, we have established state-of-the- art systems biology approaches to accurately integrate molecular data from mouse models to human cancer. By using these advanced systems approaches to interrogate our GEM models, we have identified transcriptional regulatory and epigenetic control mechanisms associated with metastasis progression. In particular, we have shown that a transcription factor pair, namely FOXM1 and CENPF, are master regulators of prostate cancer malignancy. We further demonstrate that the ETS transcription factor, ETV4, is required for metastasis. Moreover, we have found that among regulatory pathways that distinguish metastases from primary tumors are those that are associated with epigenetic modifications, such as the histone methyltransferase, SUV39H1. Thus, we have hypothesized that the molecular cascade associated with metastasis progression includes transcriptional regulatory mechanisms, which drive tumor aggressiveness and promote their metastasis, as well as epigenetic regulators, which are associated with formation of metastases. We will investigate these mechanisms as follows:
In Aim 1, we will investigate transcriptional mechanisms associated with metastasis progression, focusing on FOXM1-CENPF and ETV4, to delineate their individual functions and potential cross-talk, as well as to elucidate their mechanism(s) of action.
In Aim 2, we will investigate epigenetic regulatory mechanisms that promote metastasis, focusing on histone modifications and particularly the histone-modifying enzyme SUV39H1, to delineate its functions and mechanism(s) of action.
In Aim 3, we will pursue discovery-based systems analyses to investigate key molecular aspects of metastasis progression, in particular, to identify mechanisms associated with organ specificity of metastases and molecular mechanisms associated with clonal relationship of tumors and metastases.

Public Health Relevance

Metastasis is the primary cause of prostate cancer mortality; however, despite the pressing clinical need, there are many unresolved issues regarding the underlying biological and molecular mechanisms. Our proposed analyses using in vivo mouse models and systems approaches will elucidate transcriptional and epigenetic control mechanisms that provide coordinated control of metastatic progression. These analyses utilize novel approaches to study fundamental aspects of dissemination and metastasis and will ultimately lead to the identification of new targets for therapeutic intervention as well as new biomarkers for early detection of metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA183929-04
Application #
9399626
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2015-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Urology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Le Magnen, Clémentine; Shen, Michael M; Abate-Shen, Cory (2018) Lineage Plasticity in Cancer Progression and Treatment. Annu Rev Cancer Biol 2:271-289
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Dutta, Aditya; Le Magnen, Clémentine; Mitrofanova, Antonina et al. (2016) Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science 352:1576-80
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Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min et al. (2015) Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models. Cell Rep 12:2060-71
Abate-Shen, Cory; Pandolfi, Pier Paolo (2013) Effective utilization and appropriate selection of genetically engineered mouse models for translational integration of mouse and human trials. Cold Spring Harb Protoc 2013: