Dataset Information

A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance.

ABSTRACT: Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPK ^EYFP mice (for Nkx3.1 ^CreERT2/+ ; Pten ^flox/flox ; Kras ^LSL-G12D/+ ; R26R-CAG-^LSL-EYFP/+) develop prostate cancer with a high penetrance of metastasis to bone, thereby enabling detection and tracking of bone metastasis in vivo and ex vivo. Transcriptomic and whole-exome analyses of bone metastasis from these mice revealed distinct molecular profiles conserved between human and mouse and specific patterns of subclonal branching from the primary tumor. Integrating bulk and single-cell transcriptomic data from mouse and human datasets with functional studies in vivo unravels a unique MYC/RAS co-activation signature associated with prostate cancer metastasis. Finally, we identify a gene signature with prognostic value for time to metastasis and predictive of treatment response in human patients undergoing androgen receptor therapy across clinical cohorts, thus uncovering conserved mechanisms of metastasis with potential translational significance.

SUBMITTER: Arriaga JM

PROVIDER: S-EPMC8171279 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance.

Arriaga Juan M JM Panja Sukanya S Alshalalfa Mohammed M Zhao Junfei J Zou Min M Giacobbe Arianna A Madubata Chioma J CJ Kim Jaime Yeji JY Rodriguez Antonio A Coleman Ilsa I Virk Renu K RK Hibshoosh Hanina H Ertunc Onur O Ozbek Büşra B Fountain Julia J Jeffrey Karnes R R Luo Jun J Antonarakis Emmanuel S ES Nelson Peter S PS Feng Felix Y FY Rubin Mark A MA De Marzo Angelo M AM Rabadan Raul R Sims Peter A PA Mitrofanova Antonina A Abate-Shen Cory C

Nature cancer 20201019 11

Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPK EYFP mice (for Nkx3.1 CreERT2/+ ; Pten flox/flox ; Kras LSL-G12D/+ ; R26R-CAG-LSL-EYFP/+) develop prostate cancer with a high penetrance of metastasis to bone, thereby enabling detection and tracking of bone metastasis in vivo and ex vivo. Tr ...[more]

PMID: 34085047

Similar Datasets

Project description:BackgroundBone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC.MethodsWe comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed.ResultsA total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16).ConclusionsGDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.

Project description:BackgroundThe molecular characteristics of prostate cancer (PCa) cells and the immunosuppressive bone tumor microenvironment (TME) contribute to the limitations of immune checkpoint therapy (ICT). Identifying subgroups of patients with PCa for ICT remains a challenge. Herein, we report that basic helix-loop-helix family member e22 (BHLHE22) is upregulated in bone metastatic PCa and drives an immunosuppressive bone TME.MethodsIn this study, the function of BHLHE22 in PCa bone metastases was clarified. We performed immunohistochemical (IHC) staining of primary and bone metastatic PCa samples, and assessed the ability to promote bone metastasis in vivo and in vitro. Then, the role of BHLHE22 in bone TME was determined by immunofluorescence (IF), flow cytometry, and bioinformatic analyses. RNA sequencing, cytokine array, western blotting, IF, IHC, and flow cytometry were used to identify the key mediators. Subsequently, the role of BHLHE22 in gene regulation was confirmed using luciferase reporter, chromatin immunoprecipitation assay, DNA pulldown, co-immunoprecipitation, and animal experiments. Xenograft bone metastasis mouse models were used to assess whether the strategy of immunosuppressive neutrophils and monocytes neutralization by targeting protein arginine methyltransferase 5 (PRMT5)/colony stimulating factor 2 (CSF2) could improve the efficacy of ICT. Animals were randomly assigned to treatment or control groups. Moreover, we performed IHC and correlation analyses to identify whether BHLHE22 could act as a potential biomarker for ICT combination therapies in bone metastatic PCa.ResultsTumorous BHLHE22 mediates the high expression of CSF2, resulting in the infiltration of immunosuppressive neutrophils and monocytes and a prolonged immunocompromised T-cell status. Mechanistically, BHLHE22 binds to the CSF2 promoter and recruits PRMT5, forming a transcriptional complex. PRMT5 epigenetically activates CSF2 expression. In a tumor-bearing mouse model, ICT resistance of Bhlhe22+ tumors could be overcome by inhibition of Csf2 and Prmt5.ConclusionsThese results reveal the immunosuppressive mechanism of tumorous BHLHE22 and provide a potential ICT combination therapy for patients with BHLHE22+ PCa.

Dataset Information

A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance.

Publications

A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets