The Proteogenomic Landscape of Curable Prostate Cancer

Sinha, Ankit; Huang, Vincent; Livingstone, Julie; Wang, Jenny; Fox, Natalie S.; Kurganovs, Natalie; Ignatchenko, Vladimir; Fritsch, Katharina; Donmez, Nilgun; Heisler, Lawrence E.; Shiah, Yu Jia; Yao, Cindy Q.; Alfaro, Javier A.; Volik, Stas; Lapuk, Anna; Fraser, Michael; Kron, Ken J.; Murison, Alex; Lupien, Mathieu; Sahinalp, Cenk; Collins, Colin C.; Têtu, Bernard; Masoomian, Mehdi; Berman, David M.; Kwast, Theodorus van der; Bristow, Robert G.; Kislinger, Thomas; Boutros, Paul C.

doi:10.1016/j.ccell.2019.02.005

Cited by 183 publications

(254 citation statements)

References 75 publications

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“…This is particularly useful in diseases such as PCa, that frequently have a protracted clinical progression rate and may take years for disease recurrence and development to metastatic disease to occur. Previous proteomic studies focused on the characterization of the proteome (and transcriptome) of primary prostate cancer (Iglesias-Gato et al, 2016, Sinha et al, 2019, on proteomic and transcriptomic disease evolution (Latonen et al, 2018) or on the establishment of a diagnostic panel via machine learning (Kim et al, 2016). In contrast to the above studies, our approach is focused on the specific effects of loss of the key transcription factor STAT3 in prostate cells only.…”

Section: Discussionmentioning

confidence: 99%

STAT3-dependent systems-level analysis revealsPDK4as an independent predictor of biochemical recurrence in prostate cancer

Oberhuber¹,

Pecoraro

Rusz

et al. 2019

Preprint

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Prostate cancer (PCa) has a broad spectrum of clinical behaviour, hence biomarkers are urgently needed for risk stratification. We previously described the protective effect of STAT3 in a prostate cancer mouse model. By utilizing a gene co-expression network in addition to laser microdissected proteomics from human and murine prostate FFPE samples, we describe STAT3-induced downregulation of the TCA cycle/OXPHOS in PCa on transcriptomic and proteomic level. We identify pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging and PSA level.Furthermore, PDK4 expression is causally linked to type 2 diabetes mellitus, which is known to have a protective effect on PCa. We conclude that this effect is related to PDK4 expression and that PDK4 loss could serve as a biomarker for PCa with dismal prognosis.

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Section: Discussionmentioning

confidence: 99%

STAT3-dependent systems-level analysis revealsPDK4as an independent predictor of biochemical recurrence in prostate cancer

Oberhuber¹,

Pecoraro

Rusz

et al. 2019

Preprint

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“…Nevertheless, for both ICGC and TCGA 246 validation cohorts, the resulting prognostic subgroups had highly significantly different 247 survival rates. 248 A recent proteomics-based biomarker study of curable prostate cancer reported a stronger 249 link of DNA methylation status to protein than mRNA abundance (Sinha et al, 2019). In line 250 with these findings, we performed a validation of the clinical impact of ZIC2 as one of the 251 candidate genes on more than 12000 micro-arrayed PCa cases.…”

Section: Subsets 212mentioning

confidence: 73%

Random forest-based modelling to detect biomarkers for prostate cancer progression

Tóth

Schiffmann

Hube‐Magg

et al. 2019

Preprint

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24The clinical course of prostate cancer (PCa) is highly variable, demanding an individualized 25 approach to therapy and robust prognostic markers for treatment decisions. We present a 26 random forest-based classification model to predict aggressive behaviour of PCa. DNA 27 methylation changes between PCa cases with good or poor prognosis (discovery cohort with 28 n=70) were used as input. The model was validated with data from two large independent 29

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“…Several recent studies combining proteomic and genomic analysis have demonstrated a low degree of concordance between mRNA and protein expression (Johansson et al, 2019;Mertins et al, 2016;Sinha et al, 2019;Zhang et al, 2016) , highlighting the importance of protein-level regulation, such as recycling.…”

Section: Discussionmentioning

confidence: 99%

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

Howe

Burnette

Justice

et al. 2019

Preprint

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Manuscript Summary:Rab11b upregulation in the brain microenvironment promotes recycling of cargo proteins required for breast cancer brain metastasis, including increased surface expression of integrin β1, which allows brain extracellular matrix attachment and mechanotransduction. Inhibition of the mevalonate pathway with statins prevents geranylgeranylation of Rab11b, decreasing cargo recycling, and inhibiting brain metastasis. Declaration of Conflict of Interest:The authors declare no competing interests. 6/10/2019Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth -Google Docs https://docs.google.com/document/d/133ky5YwP8HxilKMV1nLO0styFXb_a77AufdN8Q_jytI/edit 2/27 GRAPHICAL ABSTRACT SUMMARYBreast cancer brain metastases (BCBM) have a 520 year latency and account for up to 30% of mortality.Developing new therapeutics requires a molecular understanding of adaptation to the brain microenvironment.Here, we combined RNAsequencing of BCBM development with a reverse genetic screen in Drosophila melanogaster and identified Rab11b, an endosomal recycling protein, as a mediator of metastatic adaptation.We show that disseminated cells upregulate Rab11b early after arrival in the brain, allowing control of the cell surface proteome through recycling of proteins required for successful interaction with the microenvironment, including integrin β1. Rab11bmediated control of integrin β1 surface expression allows ligation to the brain ECM, activating mechanotransduction signaling to allow survival and proliferation. We propose a model in which upregulation of Rab11b allows disseminated cells to recycle needed proteins during metastatic adaptation, without strictly requiring transcription and translation, to allow for metastatic outgrowth. 6/10/2019 Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth -Google Docs https://docs.google.com/document/d/133ky5YwP8HxilKMV1nLO0styFXb_a77AufdN8Q_jytI/edit 3/27 AUTHOR

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The Proteogenomic Landscape of Curable Prostate Cancer

Abstract: Highlights d A comprehensive proteomic analyses of localized prostate cancers d Integration of all levels of the central dogma (DNA / RNA / protein) d ETS fusions have divergent effects on transcriptome and proteome d Combining genomics and proteomics improves biomarker performance

Cited by 183 publications

References 75 publications

STAT3-dependent systems-level analysis revealsPDK4as an independent predictor of biochemical recurrence in prostate cancer

STAT3-dependent systems-level analysis revealsPDK4as an independent predictor of biochemical recurrence in prostate cancer

Random forest-based modelling to detect biomarkers for prostate cancer progression

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

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