The proteome of prostate cancer bone metastasis reveals heterogeneity with prognostic implications

Background: Bone is the most predominant site of distant metastasis in prostate cancer(PCa) and patients have limited therapeutic options at this stage. Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relief spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n=65) was used for immunohistochemical validation. Results: 5067 proteins on average were identified and quantified per tumor. Compared to primary tumors(n=26), bone metastases were more heterogeneous than and showed increased levels of proteins involved in cell cycle progression, DNA damage response, RNA processing, and fatty acid b-oxidation; and reduced levels of proteins related to cell adhesion and carbohydrate metabolism.Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of ARcanonical targets, and mitochondrialand Golgi apparatus resident proteins;and BM2,with increased expression of proliferation and DNA repair related proteins. The two subgroups, validated by the inverse correlation between MCM3 and PSA immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies. Conclusions: This work is the first system-wide quantitative characterization of the proteome of PCa bone metastases and a valuable resource for understanding the etiology of PCa progression.

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