SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression

Zhihu Ding, Chang Jiun Wu, Gerald C. Chu, Yonghong Xiao, Dennis Ho, Jingfang Zhang, Samuel R. Perry, Emma S. Labrot, Xiaoqiu Wu, Rosina Lis, Yujin Hoshida, David Hiller, Baoli Hu, Shan Jiang, Hongwu Zheng, Alexander H. Stegh, Kenneth L. Scott, Sabina Signoretti, Nabeel Bardeesy, Y. Alan WangDavid E. Hill, Todd R. Golub, Meir J. Stampfer, Wing H. Wong, Massimo Loda, Lorelei Mucci, Lynda Chin*, Ronald A. Depinho

*Corresponding author for this work

Research output: Contribution to journalArticle

314 Citations (Scopus)

Abstract

Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFÎ 2/BMPg-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.

Original languageEnglish (US)
Pages (from-to)269-276
Number of pages8
JournalNature
Volume470
Issue number7333
DOIs
StatePublished - Feb 10 2011

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Prostatic Neoplasms
Growth
Prostate
Neoplasm Metastasis
Biological Phenomena
Neoplasms
Penetrance
Cyclin D1
Prostate-Specific Antigen
Disease Progression
Epithelium
Cell Proliferation
Recurrence
Genes

ASJC Scopus subject areas

  • General

Cite this

Ding, Z., Wu, C. J., Chu, G. C., Xiao, Y., Ho, D., Zhang, J., ... Depinho, R. A. (2011). SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature, 470(7333), 269-276. https://doi.org/10.1038/nature09677
Ding, Zhihu ; Wu, Chang Jiun ; Chu, Gerald C. ; Xiao, Yonghong ; Ho, Dennis ; Zhang, Jingfang ; Perry, Samuel R. ; Labrot, Emma S. ; Wu, Xiaoqiu ; Lis, Rosina ; Hoshida, Yujin ; Hiller, David ; Hu, Baoli ; Jiang, Shan ; Zheng, Hongwu ; Stegh, Alexander H. ; Scott, Kenneth L. ; Signoretti, Sabina ; Bardeesy, Nabeel ; Wang, Y. Alan ; Hill, David E. ; Golub, Todd R. ; Stampfer, Meir J. ; Wong, Wing H. ; Loda, Massimo ; Mucci, Lorelei ; Chin, Lynda ; Depinho, Ronald A. / SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. In: Nature. 2011 ; Vol. 470, No. 7333. pp. 269-276.
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abstract = "Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGF{\^I} 2/BMPg-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100{\%} penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.",
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Ding, Z, Wu, CJ, Chu, GC, Xiao, Y, Ho, D, Zhang, J, Perry, SR, Labrot, ES, Wu, X, Lis, R, Hoshida, Y, Hiller, D, Hu, B, Jiang, S, Zheng, H, Stegh, AH, Scott, KL, Signoretti, S, Bardeesy, N, Wang, YA, Hill, DE, Golub, TR, Stampfer, MJ, Wong, WH, Loda, M, Mucci, L, Chin, L & Depinho, RA 2011, 'SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression', Nature, vol. 470, no. 7333, pp. 269-276. https://doi.org/10.1038/nature09677

SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. / Ding, Zhihu; Wu, Chang Jiun; Chu, Gerald C.; Xiao, Yonghong; Ho, Dennis; Zhang, Jingfang; Perry, Samuel R.; Labrot, Emma S.; Wu, Xiaoqiu; Lis, Rosina; Hoshida, Yujin; Hiller, David; Hu, Baoli; Jiang, Shan; Zheng, Hongwu; Stegh, Alexander H.; Scott, Kenneth L.; Signoretti, Sabina; Bardeesy, Nabeel; Wang, Y. Alan; Hill, David E.; Golub, Todd R.; Stampfer, Meir J.; Wong, Wing H.; Loda, Massimo; Mucci, Lorelei; Chin, Lynda; Depinho, Ronald A.

In: Nature, Vol. 470, No. 7333, 10.02.2011, p. 269-276.

Research output: Contribution to journalArticle

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AU - Ding, Zhihu

AU - Wu, Chang Jiun

AU - Chu, Gerald C.

AU - Xiao, Yonghong

AU - Ho, Dennis

AU - Zhang, Jingfang

AU - Perry, Samuel R.

AU - Labrot, Emma S.

AU - Wu, Xiaoqiu

AU - Lis, Rosina

AU - Hoshida, Yujin

AU - Hiller, David

AU - Hu, Baoli

AU - Jiang, Shan

AU - Zheng, Hongwu

AU - Stegh, Alexander H.

AU - Scott, Kenneth L.

AU - Signoretti, Sabina

AU - Bardeesy, Nabeel

AU - Wang, Y. Alan

AU - Hill, David E.

AU - Golub, Todd R.

AU - Stampfer, Meir J.

AU - Wong, Wing H.

AU - Loda, Massimo

AU - Mucci, Lorelei

AU - Chin, Lynda

AU - Depinho, Ronald A.

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Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011 Feb 10;470(7333):269-276. https://doi.org/10.1038/nature09677