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

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A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance
Nature Cancer ( IF 22.7 ) Pub Date : 2020-10-19 , DOI: 10.1038/s43018-020-00125-0
Juan M Arriaga ₁ , Sukanya Panja ₂ , Mohammed Alshalalfa ₃ , Junfei Zhao _{4,

5} , Min Zou _{1,

6} , Arianna Giacobbe ₁ , Chioma J Madubata _{4,

5,

7} , Jaime Yeji Kim ₁ , Antonio Rodriguez _{8,

9} , Ilsa Coleman ₁₀ , Renu K Virk ₁₁ , Hanina Hibshoosh _{11,

12} , Onur Ertunc _{13,

14,

15,

16,

17} , Büşra Ozbek _{13,

14,

15,

16} , Julia Fountain ₁₅ , R Jeffrey Karnes ₁₈ , Jun Luo _{15,

16} , Emmanuel S Antonarakis _{14,

15,

16} , Peter S Nelson ₁₀ , Felix Y Feng _{3,

19,

20,

21} , Mark A Rubin ₈ , Angelo M De Marzo _{13,

14,

15,

16} , Raul Rabadan _{4,

5,

12} , Peter A Sims _{4,

12,

22} , Antonina Mitrofanova ₂ , Cory Abate-Shen _{1,

4,

11,

12,

23}

Affiliation

Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA.
Department of Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, Newark, NJ, USA.
Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA.
Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.
Arvinas, New Haven, CT, USA.
Department of Pediatrics, Stanford University, Stanford, CA, USA.
Department for BioMedical Research, University of Bern and Inselspital, Bern, Switzerland.
Institute of Pathology, University of Bern and Inselspital, Bern, Switzerland.
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Pathology, Suleyman Demirel University, Training and Research Hospital, Isparta, Turkey.
Department of Urology, Mayo Clinic, Rochester, MN, USA.
Department of Urology, University of California at San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California at San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
Department of Urology, Columbia University Irving Medical Center, New York, NY, USA.

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.

中文翻译：

局部前列腺癌中的 MYC 和 RAS 共激活特征驱动骨转移和去势抵抗

由于体内转移的精确建模存在困难，了解致死性前列腺癌的复杂性提出了特殊的挑战。在这里，我们显示NPK ^EYFP小鼠（对于Nkx3.1 ^CreERT2/+；Pten ^flox/flox；Kras ^LSL-G12D/+；R26R-CAG - ^LSL-EYFP/+）发展为骨转移外显率高的前列腺癌，从而能够检测和跟踪体内和离体骨转移。对这些小鼠骨转移的转录组和全外显子组分析揭示了人和小鼠之间保守的不同分子谱以及原发肿瘤亚克隆分支的特定模式。将来自小鼠和人类数据集的大量和单细胞转录组数据与体内功能研究相结合，揭示了与前列腺癌转移相关的独特的 MYC/RAS 共激活特征。最后，我们确定了一个基因特征，该基因特征对转移时间具有预后价值，并可预测跨临床队列接受雄激素受体治疗的人类患者的治疗反应，从而揭示具有潜在转化意义的保守转移机制。

更新日期：2020-10-19

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