title: SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression.
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 TGFβ/BMP-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.
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Zhihu
authors.initials: Z
authors.lastname: Ding
authors.forename: Chang-Jiun
authors.initials: CJ
authors.lastname: Wu
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Dennis
authors.initials: D
authors.lastname: Ho
authors.forename: Jingfang
authors.initials: J
authors.lastname: Zhang
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Perry
authors.forename: Emma S
authors.initials: ES
authors.lastname: Labrot
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Wu
authors.forename: Rosina
authors.initials: R
authors.lastname: Lis
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: David
authors.initials: D
authors.lastname: Hiller
authors.forename: Baoli
authors.initials: B
authors.lastname: Hu
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Stegh
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Scott
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Wing H
authors.initials: WH
authors.lastname: Wong
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Lorelei
authors.initials: L
authors.lastname: Mucci
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019683:Penetrance; D011379:Prognosis; D011467:Prostate / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D051901:Smad4 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta
chemical_list: D019485:Bone Morphogenetic Proteins; C530105:Ccnd1 protein, mouse; C506895:SPP1 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C506896:Spp1 protein, mouse; D016212:Transforming Growth Factor beta; D053495:Osteopontin; D019938:Cyclin D1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D017430:Prostate-Specific Antigen