The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications

Abstract

Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage. We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve 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 ( = 65) was used for immunohistochemical validation. On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors ( = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid β-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and 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 prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies. This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. .

Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

“…The MetA and MetB subtypes show characteristics similar to the BM1 and BM2 subgroups, respectively, recently identified by proteome profiling of a subset of the bone metastases in the current study (Iglesias‐Gato et al ., ). Two important routes separating those subtypes are obviously related to cell proliferation and cell differentiation, and the metastasis phenotype might thus be predicted by combined analysis of a few markers, similarly to what is regularly done in breast cancer (Duffy et al ., ).…”

“…IR for Ki67 (or MCM, see Iglesias‐Gato et al . ()) and PSA could serve as surrogate markers for cell proliferation and differentiation, respectively, and by that differentiating less aggressive MetA from more aggressive MetB. High proliferation and low tumor cell PSA synthesis have previously been linked to poor prognosis in both primary tumors (Bubendorf et al ., ; Fisher et al ., ; Josefsson et al ., , ; Stege et al ., ) and bone metastases (Crnalic et al ., ; Iglesias‐Gato et al ., ) and recently used in combination to predict outcome in patients managed with watchful waiting (Hammarsten et al ., ).…”

“…AR‐driven bone metastases had high sterol biosynthesis, amino acid and fatty acid degradation, and nucleotide biosynthesis (Ylitalo et al ., ), while non‐androgen‐driven metastases showed high immune cell (Ylitalo et al ., ) and bone cell activities (Nordstrand et al ., ). Proteomic analysis identified two molecular subtypes of bone metastases with different phenotypes and prognosis (Iglesias‐Gato et al ., ). These observations suggest possibilities for subtype‐related treatment of bone metastatic PC.…”

“…By exploring the transcriptome and proteome of bone metastases from patients, we have identified marked differences between metastases and primary tumors and, furthermore, identified bone metastasis subgroups of apparent biological importance (Djusberg et al, 2017;H€ ornberg et al, 2011;Iglesias-Gato et al, 2018;Jernberg et al, 2013;Nordstrand et al, 2018;Ylitalo et al, 2017). Based on gene expression of canonically androgen receptor (AR) regulated genes, 80% of the examined PC bone metastases were defined as AR-driven and 20% were defined as non-AR-driven (Ylitalo et al, 2017).…”

Quantitative Proteomic Analysis of Prostate Tissue Specimens Identifies Deregulated Protein Complexes in Primary Prostate Cancer

“…Moreover, most of these studies were conducted using the two-dimensional electrophoresis (2DE) matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) technology, which rarely provides adequate proteomic coverage and is only semi-quantitative. To date, comprehensive and quantitative proteomic studies of PCa tissue specimens have remained scarce [6,[10][11][12][13][14]. Furthermore, none of these studies investigated the global changes of multiprotein complexes along PCa development and progression.…”