Identification of determinants of aggressive prostate cancer.

摘要

Prostate cancer is a heterogeneous disease arising from the epithelial cells of the prostate gland. While most prostate cancers are considered to be indolent, subsets of these cancers are or will evolve to become aggressive with heightened proliferative and invasive capacity. Two features that accompany this lethal prostate cancer phenotype are (1) androgen-independent growth and, in many cases, (2) the acquisition of neuroendocrine differentiation. Few treatments are effective at this stage and a better understanding of the disease biology is required to develop therapeutics that extend and enhance life. To this end, we set out to characterize determinants of aggressive prostate cancer, with specific focus on the epithelial cell of origin of cancer, active kinase signaling networks, and the genetics of neuroendocrine prostate cancer (NEPC).;Our group has developed technology to isolate and transform basal cells from the human prostate epithelium using lentivirus to introduce defined oncogenic alterations into benign cells prior to transplantation in mouse hosts. However, we were previously unable to assess the effect of oncogenic stress on luminal cells of the human prostate epithelium. We therefore adapted the human prostate transformation assay to use an intermediate organoid culture step to show that basal- and luminal-derived tumors arising from c-Myc overexpression and PI3K pathway activation exhibit distinct cancer differentiation states.;We have previously shown that global phosphorylation levels of tyrosine residues are increased in advanced prostate cancer relative to primary prostate cancer. To understand the active tyrosine kinase signaling networks in aggressive prostate cancer, we performed liquid chromatography tandem mass spectrometry to profile the tyrosine phosphoproteome of metastatic prostate cancer tissues obtained at rapid autopsy. We identified active and druggable targets/pathways including SRC, epidermal growth factor receptor (EGFR), rearranged during transfection (RET), anaplastic lymphoma kinase (ALK), and MAPK1/3 that may form the basis for future kinase inhibition studies in prostate cancer.;Finally, we used the human prostate transformation assay to define an important functional role for aberrant N-Myc expression in the setting of PI3K pathway activation in the initiation of NEPC. With this human NEPC model system, we established that epithelial cells can give rise to neuroendocrine cancer in the prostate gland and provided direct evidence of in vivo prostate cancer plasticity. Furthermore, N-Myc expression is required for maintenance of the cancer state and destabilizing N-Myc through inhibition of a kinase-independent interaction with Aurora A kinase may be a promising therapeutic strategy for NEPC.