Roles for Nkx3.1 in prostate cancer initiation

  • Le Magnen, Clémentine C. (PI)

Project: Research project

Project Details

Description

One of the main challenges in the management of prostate cancer remains to distinguish indolent PCa from lethal aggressive tumors. Elucidating molecular pathways governing early events leading to cancer initiation is an essential step to identify such patients and provide new opportunities for early detection and cancer prevention. Nevertheless, investigations on early stages of human cancers have been limited by the lack of experimental models and the inaccessibility to pre-neoplastic and early cancers clinical specimens.Here, we propose to use biologically relevant mouse models, cross-species analyses and pertinent functional assays to elucidate molecular events that govern early stages of prostate cancer. Specifically, we will focus on the Nkx3.1 homeobox gene, a key regulator of prostate epithelial differentiation and specification, whose loss of function is one of the earliest events of PCa initiation. Nkx3.1 represents a candidate of choice to explore mechanisms underlying cancer initiation as a result of normal development deregulation.The present study is based on the hypothesis that Nkx3.1 regulates the balance between prostate epithelial differentiation and senescence and that perturbation of this balance contributes to cancer initiation.In Aim 1, we will investigate the mechanisms governing cellular senescence as a result of Nkx3.1 loss and the consequences for blocking prostate cancer promotion. Our preliminary analyses revealed that Nkx3.1 mutant mice display senescence coincident with the occurrence of pre-neoplastic lesions. Based on these data, we will characterize the senescence phenotype in details. In particular, we will analyze the relationship between senescence and prostate cell types, define the modulators of the senescence phenotype and assess their functional relevance. Importantly, we will also investigate the clinical relevance of senescence-specific signatures in human prostate cancer.In Aim 2, we will investigate the mechanisms by which Nkx3.1 induces prostate specification and how the deregulation of this process can lead to cancer initiation. Our preliminary analyses indicate that gain-of-function of Nkx3.1 in non-prostatic epithelium is sufficient to induce prostate growth in vivo. Following these data, we will use the Nkx3.1-expressing renal graft model to identify gene expression changes associated with prostate epithelial specification. Finally, functional and clinical significance of selected genes will be assessed to identify their role in prostate epithelial specification and cancer initiation.The proposed study provides a paradigm to understand relationship between normal development and oncogenesis and addresses issues of crucial significance for various cancers.

StatusFinished
Effective start/end date2/1/141/31/16

ASJC Scopus Subject Areas

  • Cancer Research
  • Oncology

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