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

Juan M. Arriaga; Sukanya Panja; Mohammed Alshalalfa; Junfei Zhao; Min Zou; Arianna Giacobbe; Chioma J. Madubata; Jaime Yeji Kim; Antonio Rodriguez; Ilsa Coleman; Renu K. Virk; Hanina Hibshoosh; Onur Ertunc; Büşra Ozbek; Julia Fountain; R. Jeffrey Karnes; Jun Luo; Emmanuel S. Antonarakis; Peter S. Nelson; Felix Y. Feng; Mark A. Rubin; Angelo M. De Marzo; Raul Rabadan; Peter A. Sims; Antonina Mitrofanova; Cory Abate-Shen

doi:10.1038/s43018-020-00125-0

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

Juan M. Arriaga, Sukanya Panja, Mohammed Alshalalfa, Junfei Zhao, Min Zou, Arianna Giacobbe, Chioma J. Madubata, Jaime Yeji Kim, Antonio Rodriguez, Ilsa Coleman, Renu K. Virk, Hanina Hibshoosh, Onur Ertunc, Büşra Ozbek, Julia Fountain, R. Jeffrey Karnes, Jun Luo, Emmanuel S. Antonarakis, Peter S. Nelson, Felix Y. FengMark A. Rubin, Angelo M. De Marzo, Raul Rabadan, Peter A. Sims, Antonina Mitrofanova, Cory Abate-Shen

School of Medicine

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1082-1096
Number of pages	15
Journal	Nature Cancer
Volume	1
Issue number	11
DOIs	https://doi.org/10.1038/s43018-020-00125-0
State	Published - Nov 2020

ASJC Scopus subject areas

Oncology
Cancer Research

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Arriaga, J. M., Panja, S., Alshalalfa, M., Zhao, J., Zou, M., Giacobbe, A., Madubata, C. J., Kim, J. Y., Rodriguez, A., Coleman, I., Virk, R. K., Hibshoosh, H., Ertunc, O., Ozbek, B., Fountain, J., Jeffrey Karnes, R., Luo, J., Antonarakis, E. S., Nelson, P. S., ... Abate-Shen, C. (2020). A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance. Nature Cancer, 1(11), 1082-1096. https://doi.org/10.1038/s43018-020-00125-0

Arriaga, JM, Panja, S, Alshalalfa, M, Zhao, J, Zou, M, Giacobbe, A, Madubata, CJ, Kim, JY, Rodriguez, A, Coleman, I, Virk, RK, Hibshoosh, H, Ertunc, O, Ozbek, B, Fountain, J, Jeffrey Karnes, R, Luo, J, Antonarakis, ES, Nelson, PS, Feng, FY, Rubin, MA, De Marzo, AM, Rabadan, R, Sims, PA, Mitrofanova, A & Abate-Shen, C 2020, 'A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance', Nature Cancer, vol. 1, no. 11, pp. 1082-1096. https://doi.org/10.1038/s43018-020-00125-0

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title = "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 NPKEYFP mice (for Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-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.",

author = "Arriaga, {Juan M.} and Sukanya Panja and Mohammed Alshalalfa and Junfei Zhao and Min Zou and Arianna Giacobbe and Madubata, {Chioma J.} and Kim, {Jaime Yeji} and Antonio Rodriguez and Ilsa Coleman and Virk, {Renu K.} and Hanina Hibshoosh and Onur Ertunc and B{\"u}{\c s}ra Ozbek and Julia Fountain and {Jeffrey Karnes}, R. and Jun Luo and Antonarakis, {Emmanuel S.} and Nelson, {Peter S.} and Feng, {Felix Y.} and Rubin, {Mark A.} and {De Marzo}, {Angelo M.} and Raul Rabadan and Sims, {Peter A.} and Antonina Mitrofanova and Cory Abate-Shen",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = nov,

doi = "10.1038/s43018-020-00125-0",

language = "English (US)",

volume = "1",

pages = "1082--1096",

journal = "Nature Cancer",

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T1 - A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance

AU - Arriaga, Juan M.

AU - Panja, Sukanya

AU - Alshalalfa, Mohammed

AU - Zhao, Junfei

AU - Zou, Min

AU - Giacobbe, Arianna

AU - Madubata, Chioma J.

AU - Kim, Jaime Yeji

AU - Rodriguez, Antonio

AU - Coleman, Ilsa

AU - Virk, Renu K.

AU - Hibshoosh, Hanina

AU - Ertunc, Onur

AU - Ozbek, Büşra

AU - Fountain, Julia

AU - Jeffrey Karnes, R.

AU - Luo, Jun

AU - Antonarakis, Emmanuel S.

AU - Nelson, Peter S.

AU - Feng, Felix Y.

AU - Rubin, Mark A.

AU - De Marzo, Angelo M.

AU - Rabadan, Raul

AU - Sims, Peter A.

AU - Mitrofanova, Antonina

AU - Abate-Shen, Cory

PY - 2020/11

Y1 - 2020/11

N2 - Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPKEYFP mice (for Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-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.

AB - Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPKEYFP mice (for Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-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.

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JO - Nature Cancer

JF - Nature Cancer

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ER -

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

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